Nutrition, Metabolism & Cardiovascular Diseases (2022) 32, 1e16

Available online at www.sciencedirect.com

Nutrition, Metabolism & Cardiovascular Diseases

journal homepage: www.elsevier.com/locate/nmcd

PRACTICE GUIDELINES

Non-alcoholic fatty liver disease in adults 2021: A clinical practice

guideline of the Italian Association for the Study of the Liver (AISF),
the Italian Society of Diabetology (SID) and the Italian Society of
Obesity (SIO)*
Associazione Italiana per lo Studio del Fegato (AISF), Società Italiana di Diabetologia
(SID) and Società Italiana dell’Obesità (SIO)1

Received 26 April 2021; accepted 28 April 2021

Available online 16 December 2021

KEYWORDS Abstract Nonalcoholic fatty liver disease (NAFLD) is a common and emerging liver disease in
NAFLD; adults, paralleling the epidemic of obesity and diabetes, and leading to worrisome events (hepa-
NASH; tocellular carcinoma and end-stage liver disease). In the last years, mounting evidence added in-
Guidelines sights about epidemiology, natural history, diagnosis and lifestyle-based or drug treatment of
NAFLD. In this rapidly evolving scenario, members of the Associazione Italiana per lo Studio
del Fegato (AISF), the Società Italiana di Diabetologia (SID) and the Società Italiana dell’Obesità
(SIO) reviewed current knowledge on NAFLD. The quality of the published evidence is graded,
and practical recommendations are made following the rules and the methodology suggested
in Italy by the Centro Nazionale per l’Eccellenza delle cure (CNEC) and Istituto Superiore di Sanità
(ISS). Whenever possible, recommendations are placed within the context the Italian Healthcare
system, with reference to specific experience and local diagnostic and management resources.

Level of evidence: Level of evidence of recommendations for each PICO question were re-
ported according to available evidence.
ª 2021 The Authors. Published by Elsevier B.V. on behalf of The Italian Diabetes Society, the Ital-
ian Society for the Study of Atherosclerosis, the Italian Society of Human Nutrition and the
Department of Clinical Medicine and Surgery, Federico II University. This is an open access article
under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/).

Introduction diagnosis and treatment of non-alcoholic fatty liver dis-

The present report is a summary of Clinical Practice
Guidelines resulting from a cooperative work of the
Associazione Italiana per lo Studio del Fegato (AISF), the
Società Italiana di Diabetologia (SID) and the Società
Italiana dell’Obesità (SIO). Current knowledge on the
ease (NAFLD) is translated into relevant practical recom-
mendations for management following the rules and the
methodology suggested in Italy by the Centro Nazionale
per l’Eccellenza delle cure (CNEC) and Istituto Superiore
di Sanità (ISS). In this summary, we report the outline of
disease burden and the risks associated with disease

*
This article is co-published in the journals: Digestive and Liver Disease https://doi.org/10.1016/j.dld.2021.04.029; Nutrition, Metabolism &
Cardiovascular Diseases https://doi.org/10.1016/j.numecd.2021.04.028 and Eating and Weight Disorders - Studies on Anorexia, Bulimia and Obesity
https://doi.org/10.1007/s40519-021-01287-1.
1
The members of the guidelines panel are listed in Appendix 2.
Correspondence: S. Petta.
E-mail addresses: info@webasif.org, salvatore.petta@unipa.it.

https://doi.org/10.1016/j.numecd.2021.04.028
0939-4753/ª 2021 The Authors. Published by Elsevier B.V. on behalf of The Italian Diabetes Society, the Italian Society for the Study of Atherosclerosis, the Italian Society of
Human Nutrition and the Department of Clinical Medicine and Surgery, Federico II University. This is an open access article under the CC BY-NC-ND license (http://
creativecommons.org/licenses/by-nc-nd/4.0/).

Descargado para Anonymous User (n/a) en Antenor Orrego Private University de ClinicalKey.es por Elsevier en julio 05, 2024. Para uso
personal exclusivamente. No se permiten otros usos sin autorización. Copyright ©2024. Elsevier Inc. Todos los derechos reservados.
2 Members of the guidelines panel
progression, followed by PICO questions and recom-
mendations. The review of the literature at the basis of
individual recommendations is uploaded as supplemen-
tary material.
Burden of disease and risk factors
The natural history of nonalcoholic fatty liver disease
(NAFLD) has been extensively investigated in the past 20
years [1,2]. Steatosis is the hallmark of NAFLD and has been
identified as an independent risk factor for the full spec-
trum of liver damage including inflammation, ballooning
and fibrosis [3]. The diagnosis of NAFLD requires the
exclusion of both secondary causes and of alcohol con-
sumption 30 g per day for men and 20 g per day for
women [4]. Recently, a consensus of experts proposed to
overcome the current nomenclature “NAFLD” and adopt
for a “positive” definition the acronym Metabolic
dysfunction-Associated Fatty Liver Disease (MAFLD) using
metabolic dysfunctions as diagnostic criteria indepen-
dently of the presence of other causes of chronic liver
disease [5]. The mean prevalence of NAFLD worldwide is
24.1%, ranging from 13.5% in Africa to 31.8% in Middle East,
with differences among studies also related to diagnostic
methods, age, gender and ethnicity [1]. Italian studies
indicate a prevalence of 22.5e27.0% in the general popu-
lation [6e9], with a 2% prevalence of noninvasively-
assessed advanced fibrosis due to NAFLD [9]. The preva-
lence increases in patients with metabolic comorbidities
and the metabolic syndrome (MetS), defined by the presence
of at least three metabolic alterations among elevated waist
circumference (94 cm in males; 80 cm in females in
Europids), elevated triglycerides (150 mg/dL), reduced
HDL-C (40 mg/dL in males; 50 mg/dL in females),
elevated blood pressure (systolic pressure 130 mmHg and/
or diastolic pressure 85 mm or antihypertensive drug
treatment) and elevated fasting glucose (100 mg/dL anti-
hyperglycemic treatment) [10]. NAFLD is observed in
54e90% [9,11] and 78.8% [12] of cases with obesity or with
MetS, respectively. In the Dionysos study, the presence of
steatosis was closely associated with obesity [13] and in
the Dionysos and Nutrition Liver Study the risk of NAFLD
was 9-fold increased by the presence of BMI  30 kg/m2
and 6-fold by abdominal obesity (waist circumference
102 cm in males, 88 in females) [6], independently of
altered liver enzymes. Raised liver enzymes, assumed as
surrogate indexes of NAFLD, were reported in 21% of cases
with obesity and did not increase systematically with
obesity class [14]. In a more recent analysis of 890 subjects
of the community-based ABCD (“Alimentazione, Benessere
Cardiovascolare e Diabete”) study, Petta et al. reported a
NAFLD prevalence of 48%, with a relative risk for obesity of
4.02 (95% confidence interval, 2.77e5.84) [9], but the
various diagnostic tools and/or settings may provide
slightly different results.
The prevalence of NAFLD is as high as 70e80% in pa-
tients with type 2 diabetes mellitus (T2DM) [15,16], who
are also more likely to have nonalcoholic steatohepatitis
(NASH) and cirrhosis, even in the presence of fairly normal
Descargado para Anonymous User (n/a) en Antenor Orrego Private University de ClinicalKey.es por Elsevier en julio 05, 2024. Para uso
personal exclusivamente. No se permiten otros usos sin autorización. Copyright ©2024. Elsevier Inc. Todos los derechos reservados.
serum aminotransferase levels [16e18]. In Italian patients
with diabetes NAFLD is reported in 59.0e73.2% [19,20],
with about 13%-18% of them experiencing advanced
fibrosis [21]. A bidirectional association exists between
NAFLD and T2DM [17,22], worsening the course of both
diseases; the presence of T2DM increases the risk of
NAFLD progression to advanced fibrosis and cirrhosis, as
well as also of incident hepatocellular carcinoma (HCC),
liver-related hospital admissions and liver-related deaths
[17,23e25], whereas the presence of NAFLD in T2DM is
associated with a reduced probability of achieving good
glycemic control, and exacerbates atherogenic dyslipide-
mia, further increasing the risk of chronic kidney disease
and adverse CV outcomes [17,18], particularly in the pres-
ence of NASH-fibrosis [26].
The lifetime costs of all NASH patients in the United
States in 2017 is estimated at $222.6 billion, and the cost of
the advanced NASH population at $95.4 billion [27]. Data
from Italian local Health Units, based on administrative
data and resources utilization, calculated an average direct
cost for NAFLD/NASH progressively increasing from the
non-advanced stage, to advanced NAFLD disease,
compensated cirrhosis, liver transplant, and hepatocellular
carcinoma (HCC), also driven by comorbidities, up to over
V 65.000/year [28]. Considering the projections calculated
by disease modeling for the next decades, the total costs is
likely to become very challenging for the National Health
system [29].
NAFLD mortality and morbidity
Patients with NAFLD have an increased overall mortality
compared to matched control populations [30,31]. Accord-
ing to a meta-analysis, overall mortality was reported to be
15.4 per 1,000 person-years (range, 11.7e20.3) for patients
with NAFLD and 25.6 (range, 6.3e103.8) for the cohort with
NASH [1]. The presence of NASH (adjusted hazard
ratioadjHR], 9.16), age (adjHR, 1.06), and the presence of T2DM
(adjHR, 2.09) increased all-cause and liver-related mortality,
after controlling for other variables. Liver-specific mortality
was estimated as 0.8 (range, 0.3e1.8) in NAFLD and 11.8
(range, 7.1e19.5) in NASH [1]. Cardiovascular (CV) disease
(CVD) remains the most common cause of death, indepen-
dent of other metabolic comorbidities [32,33], driven by the
atherogenic profile and widespread CV complications
[33e35], independently of other known risk factors [36,37].
Fibrosis stage is the strongest predictor for mortality from
CVD and liver-related disease in a cohort of biopsy-proven
NAFLD after up to 33 years of follow-up [38].
NAFLD is also associated with an approximate 2-fold
increased risk of incident T2DM, ranging from a 35% to a
5.5-fold increase, independent of overweight/obesity and
other common risk factors [34,39]. The risk of incident
T2DM appears to diminish over time following the
improvement or resolution of NAFLD [40,41]. Patients with
NAFLD also have a nearly 40% increase in the long-term
risk of incident chronic kidney disease [42], as well as
other recognized associations with sleep apnea, osteopo-
rosis, psoriasis and endocrinopathies [43].
Practice Guidelines
The presence of NASH increases liver-related mortality
[44,45], but the most important driver of mortality is
fibrosis at histology, specifically, zone 3 sinusoidal fibrosis
plus periportal fibrosis (stage 2), advanced fibrosis
(bridging fibrosis [stage 3] or cirrhosis [stage 4]) [2,46],
associated with the multiple component of MetS [47].
Patients with stage 4 fibrosis (cirrhosis) had a nearly 10-
fold risk of liver-related complications [2], with liver-
related events occurring in 8.9 per 100 person-years
(95% CI, 6.7e11.7]. The reported annual incidence of he-
patic decompensation was 3.3 and 15.6 per 100 person-
years among patients with Child Pugh (CP)-A5 and CP-A6
cirrhosis, respectively [48].
Hepatocellular carcinoma and extrahepatic cancers
NAFLD is the third-most common cause of HCC in the
United States, after hepatitis C and alcohol-related disease,
accounting for 14.1% of all cases [49]. The cumulative
incidence of NAFLD-associated HCC has been reported to
range from 2.4% to 12.8% over a median follow-up period
of 3.2e7.2 years [50], corresponding to 0.44 (range,
0.29e0.66) per 1000 person-years and increasing at a 9%
annual rate [1,49,51]. Patients with NAFLD fibrosis stages
F3 and F4 have an almost 7-fold increased risk of HCC
compared to people without liver disease [49] and the risk
is >10 folds higher in association with T2DM and obesity
[52], making NAFLD the second leading cause of liver
transplantation (LT) due to HCC in U.S and the most rapidly
increasing indication [53]. At diagnosis, patients with
NAFLD-related HCC are older, have higher prevalence of
extrahepatic comorbidities but lower prevalence of
cirrhosis (absence of cirrhosis in up to 1/3 of cases), and
shorter survival time [50], being more likely to die from
their primary liver cancer than other HCC patients [49].
These conditions may be driven by less systematic sur-
veillance, leading to diagnosis at later stage and less
treatment [54].
Other extra-hepatic cancers are similarly increased,
namely cancers of the uterus (IRRZ2.3; 95%CI 1.4, 4.1),
stomach (IRRZ2.3; 95%CI 1.3, 4.1), pancreas (IRRZ2.0; 95%
CI 1.2, 3.3) and colon (IRRZ1.8; 95%CI 1.1, 2.8) [54]. The as-
sociation with cancer risk is stronger in NAFLD than in
obesity [55].
Lean NAFLD
The term ‘lean’ NAFLD refers to patients with a BMI within
the ethnic-specific cut-off of normalweight, but frequently
extended to the area of overweight (30 kg/m2 in Caucasian
and 27 kg/m2 in Asian subjects). It is conceivable that ‘lean’
NAFLD comprises an heterogeneous NAFLD cohort asso-
ciated with environmental and genetic factors, as well as
differences in fat distribution and body composition [56],
accounting for 5e26% of total NAFLD cases in the Asian
population and 7e20% in the Western areas [56]. A recent
meta-analysis of 33 observational studies from 14 countries
concluded for a global prevalence of NAFLD in lean in-
dividuals (BMI  23 kg/m2 for Asian subjects and BMI 
Descargado para Anonymous User (n/a) en Antenor Orrego Private University de ClinicalKey.es por Elsevier en julio 05, 2024. Para uso
personal exclusivamente. No se permiten otros usos sin autorización. Copyright ©2024. Elsevier Inc. Todos los derechos reservados.
3
25 kg/m2 for non-Asian subjects) of 9.7% (95% CI: 7.7e11.8%),
with an upward trend between 1988 and 2017[57]. Their
rate of comorbidity is lower compared to obese patients,
but higher compared to healthy controls [58,59]. Data on
histological severity are controversial; they can develop
the full spectrum of liver disease associated with NASH
[60] and similar adverse health outcomes when longitu-
dinally examined [61,62].
Methods for guideline development
Following the needs of an updated guidance upon clinical
management of the Non Alcoholic Fatty Liver Disease, the
Scientific Societies whose members are primarily involved in
its management (Italian Association for the Study of the Liver
- AISF; Italian Society of Diabetology - SID; Italian Society of
Obesity - SIO) commissioned to an experts panel the drafting
of a new dedicated document to outline the updated clinical
practice guidelines. The present document was made ac-
cording to the rules dictated by the Italian Center for the Cure
Excellence (Centro Nazionale per l’Eccellenza delle Cure -
CNEC), an institution recently set up by the Italian National
Institute of Health (Istituto Superiore di Sanità - ISS) to
outline the methodologies needed to provide evidence-
based clinical, diagnostic and therapeutic guidelines in Italy
[63]. According to these rules, a “multi-societary” and “multi-
disciplinary” committee of experts was selected by the
abovementioned Scientific Societies. The committee defined
the objectives, the key issues and retrieved the relevant evi-
dences by performing a systematic review of literature.
Finally, the committee members (chosen on the basis of their
specific expertise) identified the guidelines’ key questions
and developed them following the PICO format (Population,
Intervention, Comparison, Outcomes) [64]. The most rele-
vant questions were chosen by voting among the whole
committee. The mean agreement among panel members on
recommendations was 98.15%, as reported in supplementary
Table 1. For each PICO question, a systematic review of the
literature was made on the most important scientific data-
bases (Pubmed, Scopus, Embase) by performing both a free-
text research and by a BOOLEAN research string formulated
on purpose (see Appendix 1). The profiles of evidence were
developed by applying the GRADE-Evidence to Decision
(EtD) frameworks as per CNEC manual indications [63,65]. In
particular, all aspects regarding the questions, the assess-
ment of evidence and the conclusions drawings were dis-
cussed between the panel members and voted to obtain a
final decision. The GRADEpro GDT online tool was used to
develop the questions and make the decisions [66]. The
quality of evidence was evaluated by applying the “Quality
Assessment of Diagnostic Accuracy Studies version 2”
(QUADAS-2) checklist for the diagnostic accuracy questions
[67], the “revised tool for Risk of Bias in randomized trials”
(RoB 2) [68] and the “Risk Of Bias in Non-randomized Studies
- of Interventions” tool (ROBINS-I) [69] for randomized clin-
ical trials and non-randomized studies where applicable.
The final draft was submitted for advice and revision to
EpaC (Liver Patients’ Association). Their comments were
considered in the final version.
4 Members of the guidelines panel
Strength and limits
The present report is a summary of Clinical Practice
Guidelines resulting from a cooperative multi-society
work and by using rigorous methodology suggested in
Italy by the Centro Nazionale per l’Eccellenza delle cure
and Istituto Superiore di Sanità. Lack of awareness for
NAFLD and obstacles to apply and implement guidelines
could limit their utility.
What is already known on this subject?
NAFLD is an emerging liver disease with a growing
epidemiological and clinical burden.
National guidelines for the management of NAFLD pa-
tients are not still available.
What this study adds?
The present document is the first effort to provide multi-
society national guidelines on NAFLD aimed to a multidisci-
plinary and shared management of NAFLD patients.
PICO Questions and recommendations
(A) Assessment of disease severity
PICO 1 - In adult patients with NAFLD, should non-invasive
scores, serum markers, liver stiffness, and imaging methods be
used as replacement for liver biopsy for the diagnosis of NASH?
Recommendation
 In patients with NAFLD non-invasive tests do not have
acceptable accuracy for the diagnosis of NASH, and liver
biopsy remains the reference standard (B,2).
References: [4,70e75]
PICO 2 - In adult patients with NAFLD, should non-
invasive scores, serum markers, liver stiffness, and imaging
methods be used as replacement for liver biopsy for the
diagnosis of advanced fibrosis?
Recommendations
 In patients with NAFLD, simple noninvasive scores,
namely the Fibrosis-4 score (FIB-4) and the NAFLD
fibrosis score (NFS), as well as liver stiffness measure-
ment (LSM), using transient elastography, have
acceptable accuracy to identify NAFLD cases at low risk
of advanced fibrosis (A, 1).
 A two-tier sequential combination of simple noninva-
sive scores like FIB-4 or NFS with imaging techniques
such as LSM by transient elastography is recommended
as a triage test for ruling out advanced fibrosis sparing
further testing (B, 2).
 Magnetic resonance elastography (MRE) is the most
accurate noninvasive method for estimation of liver
fibrosis. This technique can be preferred in clinical
Descargado para Anonymous User (n/a) en Antenor Orrego Private University de ClinicalKey.es por Elsevier en julio 05, 2024. Para uso
personal exclusivamente. No se permiten otros usos sin autorización. Copyright ©2024. Elsevier Inc. Todos los derechos reservados.
trials, but it is not recommended in clinical practice,
being expensive and very rarely available (B, 2).
References: [76e102]
Fig. 1 depicts a two-step algorithm, based on FIB-4 or
NAFLD fibrosis score as first step followed by LSM, pro-
posed for the assessment of fibrosis severity in patients
with NAFLD.
PICO 3 - In adult patients with NAFLD, should non-
invasive scores, liver stiffness and imaging methods be used
as replacement for liver biopsy for predicting liver-related
outcomes?
Recommendations
 In patients with NAFLD, non-invasive tools might
acceptably rule out fibrosis progression (C, 2).
 In patients with NAFLD, noninvasive tools might
acceptably predict the risk of occurrence of overall and
liver-related events and mortality (C, 2).
References: [36,103e113]
PICO 4 - In adult patients with NAFLD, should genetic
testing be used as an add on after usual testing in predicting
the severity of histologically-assessed liver damage and liver-
related outcomes?
Recommendations
 Clinicians in referral centers might consider the genetic
risk profile for stratification of individual NAFLD-HCC
risk, but the effectiveness of such strategy requires
larger prospective studies (C, 2).
 We suggest that genetic risk variants be evaluated in
clinical studies for stratification of disease risk pro-
gression and sub-phenotyping of NAFLD (B, 2).
References: [3,4,114e124]
Supplementary Table 2
(B) Weight loss and behavioral intervention for NAFLD
PICO 5 - In adult patients with NAFLD, what is the efficacy
of weight loss on histologically-assessed liver damage and
liver-related outcomes in comparison with no intervention?
Recommendations
 All subjects with NAFLD, including lean (non-obese)
NAFLD, should be involved in lifestyle programs
aimed at healthy diet and habitual physical activity
to a 7e10% weight loss target, repeatedly associ-
ated with improved histology, including fibrosis (B,
1).
 The dietary approach to NAFLD should favor adherence
to the principles of the Mediterranean diet, including a
reduced intake of refined and industrial sugars, asso-
ciated with reduced hepatic fat content and decreased
cardiovascular risk (B, 1).
 Low-modest alcohol intake in noncirrhotic NAFLD pa-
tients should not be encouraged (C, 2) and total absti-
nence in NAFLD-cirrhosis is recommended (B, 1).
Practice Guidelines 5

Fig. 1 1NAFLD is defined by ultrasound; in case of difficult access to ultrasound, clinicians can directly screen patients with features of metabolic
syndrome by liver enzymes and noninvasive scores of fibrosis.
2
AST, ALT, GGT
Note that in patients referred to specialists (right side) follow-up will depend on disease severity/available therapeutic protocols; timing of follow-up
in negative patients (left side) will depend on the presence of metabolic factors and comorbid conditions.

 In patients with NAFLD, any types of physical activity, as
well as reduced sedentariness, should be counseled, in
order to reduce liver fat, independently of changes in
body weight (B, 1).
 Clinicians should recommend weight loss by intensive,
structured lifestyle programs delivered under specialist
control and/or pharmacotherapy and/or bariatric surgery
in NAFLD subjects with obesity to reduce liver disease
severity (A, 1).
References: [9,125e176]
(C) Pharmacologic treatment for NAFLD
The epidemic of NAFLD and its complications, and the
discovery of different potential therapeutic targets for NASH
treatment led to start an impressive number of clinical trials.
International guidelines recommend that pharmacological
therapy for NAFLD/NASH should be reserved to patients
presenting an active disease and the presence of liver fibrosis
 stage 2 [177,178]. Moreover, the FDA (US Food and Drug
Administration) and the EMA (European Medicines Agency)
identified two endpoints for the conditional approval of drugs
in patients with noncirrhotic NASH: (1) resolution of NASH
without worsening of liver fibrosis, and (2) at least one stage
improvement in liver fibrosis without worsening of NASH
fibrosis [178]. Consistently, most of the phase 2b and phase 3
trials enrolled patients with NASH plus fibrosis stage F2-F3.
However, in spite of a large number of published or ongoing
clinical trials, to date neither FDA, nor EMA or AIFA have
approved any pharmacological treatment for patients with
NASH.
PICO 6 - In adult patients with NAFLD, what is the efficacy
of pharmacological treatment on histologically-assessed liver
damage and liver-related outcomes in comparison with no
pharmacological intervention?
Recommendations
 In patients with NASH pioglitazone may be used to
improve NASH and fibrosis, although the drug is off-
label and the risk/benefit balance related to pioglita-
zone side-effects should be discussed with each patient
(B, 2).
 In patients with NASH vitamin E may be used to
improve NASH and fibrosis, even if risks and benefits
should be discussed with each patient (B, 2).
 In patients with NASH standard or high-dose ursodeox-
ycholic acid (UDCA) should not be used to treat NASH and
fibrosis, because ineffective (B, 2).
 In patients with NASH obeticholic acid may improve
fibrosis without worsening of NASH, but its use is
waiting for approval by regulatory agencies, based on
additional safety and efficacy data (B, 2).
References for pioglitazone: [179e194]
References for vitamin E: [182,195e202]

Descargado para Anonymous User (n/a) en Antenor Orrego Private University de ClinicalKey.es por Elsevier en julio 05, 2024. Para uso
personal exclusivamente. No se permiten otros usos sin autorización. Copyright ©2024. Elsevier Inc. Todos los derechos reservados.
6 Members of the guidelines panel
References for ursodeoxycholic acid: [203e206]
References for obeticholic acid: [207e209]
PICO 7 - In adult patients with NAFLD and type 2 diabetes
mellitus, what is the efficacy of glucose-lowering treatment
on histologically-assessed liver damage and liver-related
outcomes?
Recommendations
 In T2DM patients with NAFLD/NASH, pioglitazone is
specifically recommended to treat liver disease (B, 2).
 In T2DM patients with NAFLD/NASH, metformin use is
safe for the liver, but it is not specifically recommended
to treat liver disease (B, 2).
 In T2DM patients with NAFLD/NASH, DPP-4 inhibitors
are safe for the liver, but their use is not specifically
recommended to treat liver disease (C, 2).
 In T2DM patients with NAFLD/NASH, GLP-1 receptor
agonists are safe for the liver, but, despite preliminary
evidence that may decrease liver damage, their use is
not specifically approved to treat liver disease (B, 2).
 In T2DM patients with NAFLD/NASH, SGLT-2 inhibitors
are safe for the liver, but their use is not specifically
recommended to treat liver disease (C, 2).
References for metformin: [185,210e215]
References for DPP-4 inhibitors: [216e220]
References for GLP-1 receptor agonists:
[141,219,221e228]
References for SGLT-2 inhibitors: [229e239]
(D) NAFLD and liver transplantation
PICO 8 - In adult patients with NASH candidate for liver
transplantation, should the evaluation of cardiometabolic
comorbidities in the pre- and post-transplant phase be
different from that of patients with liver disease of other
etiology in order to reduce cardiovascular complications?
Recommendations
 In liver transplant candidates with NASH-related
decompensated cirrhosis or NASH-HCC, both at partic-
ularly high risk of developing cardiovascular events,
cardiovascular risk factors should be assessed by a
multidisciplinary team, which includes a transplant
cardiologist and a transplant anesthesiologist, but no
universally validated algorithms are available for a
comprehensive evaluation (C, 1).
 Thorough screening for hypertension, diabetes, and
dyslipidemia is recommended in patients with NASH
undergoing evaluation for liver transplantation and
appropriate medical treatment in wait-listed patients is
mandatory to reduce events and de-listing (B, 1).
 Obesity alone does not constitute a contraindication for
liver transplantation. Patients with decompensated
NASH-cirrhosis or NASH-HCC and morbid obesity (body
Descargado para Anonymous User (n/a) en Antenor Orrego Private University de ClinicalKey.es por Elsevier en julio 05, 2024. Para uso
personal exclusivamente. No se permiten otros usos sin autorización. Copyright ©2024. Elsevier Inc. Todos los derechos reservados.
mass index > 40 kg/m2 should be listed on a highly
individualized basis, especially in the presence of dia-
betes (B, 2).
References: [37,54,240e254]
PICO 9 - In adult patients with NASH and morbid obesity,
candidate for liver transplantation, what is the efficacy of
bariatric surgery on pre- and post-transplant outcomes in
comparison with no bariatric surgery?
Recommendation
 Bariatric surgery may improve outcomes in
patients with morbid obesity in the setting of liver
transplantation, however in decompensated cirrhosis it
is associated with higher risk of morbidity and mor-
tality; too few data are available to recommend the
procedure before, during or after transplantation (C, 2).
References: [255e263]
(E) NAFLD ascertainment in the general population
PICO 10 - In the adult population are non-invasive scores
and imaging methods useful for the diagnosis of NAFLD?
Recommendations
 Non-invasive scores (Fatty Liver Index e FLI) may be
useful in population studies for the diagnosis of stea-
tosis (A, 1).
 Ultrasonography (US) is the first-line diagnostic pro-
cedure for detecting NAFLD, as it has high accuracy for
moderate-severe steatosis and also provides additional
diagnostic information (A, 1).
 1H-Magnetic Resonance Spectroscopy (MRS) is the
reference standard for a quantitative estimation of liver
fat. This technique should be preferred in clinical trials,
but it is not recommended in clinical practice because
expensive and not largely available (A, 2).
 Controlled Attenuation Parameter (CAP) is an alterna-
tive tool for non-invasive assessment and follow-up of
steatosis but more data are needed to definitively
define its role (B,2).
References: [264e276]
PICO 11 - In adult population with metabolic risk factors
are non-invasive scores, liver stiffness and imaging methods
useful for the diagnosis of advanced fibrosis?
Recommendation
 In adult individuals with one or more features of the
metabolic syndrome, a combination of non-invasive
fibrosis markers may help improve referral of patients
with advanced liver fibrosis from primary care to specialist
setting, also reducing the cost of management (B, 2).
References: [16,48,277e283]
Practice Guidelines
Conclusion
In the past few years NAFLD emerged as a common liver
disease in adults frequently associated with metabolic al-
terations, and as a leading cause of HCC and liver decom-
pensation, finally impacting resource utilization and costs
of the Healthcare systems. Also in Italy, the cost associated
with NAFLD for the National Health System is rapidly
increasing [28]. The growing interest for NAFLD lead to the
development of new diagnostic tools and algorithms to
identify and refer patients at high risk of liver damage to
liver specialists for assessment and treatment. The
implementation of lifestyle programs aimed at weight loss
and ongoing clinical trials with drugs targeting pathogenic
pathways responsible for necroinflammation and fibrosis
open new scenario in the management of NAFLD patients
[284].
The present Guidelines are conceived to promote a
fruitful collaboration between different specialties, in a
multidisciplinary approach aimed at disseminating and
improving treatment within the healthcare professionals.
Given the impressive amount of research and the
extraordinary advances of the past few years, the several
attempts to define new treatment strategies and the large
number of trials supported by pharmaceutical companies,
the proposed recommendations should be considered
provisional and the Writing Commission recommends
systematic update of Guidelines at regular intervals.
Finally, given its epidemiological, clinical and eco-
nomic burden, NAFLD should be classified as a definite
liver disease by the Health Care Italian System, inde-
pendently of the presence of other metabolic comorbid-
ities, with appropriate regulations in terms of diagnosis
and treatment.
Declaration of competing interest
Giulio Marchesini participated in NAFLD advisory boards
of Astra-Zeneca, Pfizer, Gilead, Novartis and received
honoraria for conference from Eli Lilly
Elisabetta Bugianesi: Consultant for Gilead, BMS, Boer-
ingher, Intercept, Innova, Novo Nordisk
Patrizia Burra received personal fees from Biotest,
Kedrion and Chiesi Farmaceutici for occasional scientific
collaboration
Fabio Marra: Abbvie: consultant fees; Allergan:
consultant fees; AstraZeneca: consultant fees; Gilead:
speaker honoraria, consultant fees; Intercept: speaker
honoraria; Menarini: consultant fees; Novartis: consultant
fees; Novo Nordisk: consultant fees
Luca Miele: Advisory Board, Consultancy, Invited
Speaker: Alfa-Sigma, Boehringer-Ingelheim, BMS, Echos-
ens, Galmed, Gilead Sciences, IBSA, Intercept, MEDA,
MyGenomics, Merck Sharp & Dohme, Novartis, Pfizer,
ProLon, Promethera, Rottapharm-Madaus, Siemens
Healthineers, Synageva
Descargado para Anonymous User (n/a) en Antenor Orrego Private University de ClinicalKey.es por Elsevier en julio 05, 2024. Para uso
personal exclusivamente. No se permiten otros usos sin autorización. Copyright ©2024. Elsevier Inc. Todos los derechos reservados.
7
Anna Alisi: no disclosures
Piero Vajro: no disclosures
Mario Masarone: Gilead travel grants, invited speech;
Abbvie: travel grants, invited speech, advisory boards
Salvatore Petta: Advisor and/or Speaker for Abbvie,
Gilead, Intercept and Pfyzer
Marcello Persico acted as consultant for Abbvie and
Gilead
Gianluca Svegliati-Baroni: no disclosures
Luca Valenti: Speaking: MSD, Gilead, AlfaSigma, Abb-
Vie; Consulting: Gilead, Pfizer, Astra Zeneca, Novo Nordisk,
Intercept pharmaceuticals, Diatech Pharmacogenetics,
IONIS; Research: Gilead
Massimo Federici: no disclosures
Francesco Purrello: no disclosures
Ferdinando Carlo Sasso has been member of Advisory
Boards for Boehringer and for Ely-Lilly and has received
fees for scientific consultation and/or lectures by
Jansen, Roche Diagnostics, Novo Nordisk, Sanofi, MSD,
Astrazeneca
Giovanni Targher: no disclosures
Luca Busetto: no disclosures
Maria Letizia Petroni: no disclosures
Ferruccio Santini has worked as a consultant, partici-
pated in studies, and/or received travel funds from the
following companies, which are involved with obesity and
related diseases: AstraZeneca, Aegerion Pharmaceuticals,
Amryt, BioItalia, Bruno farmaceutici and Novo Nordisk.
Calogero Cammà: no disclosures
Agostino Colli: no disclosures
Acknowledgments
The Italian Association for the Study of Liver disease is
indebted to Ivan Gardini and EpaC Onlus (Liver Patients’
Association) for advice and revision of the manuscript.
Their suggestions have been considered in the final
version.
Supplementary materials
Supplementary material associated with this article can be
found, in the online version, at doi.org/10.1016/j.numecd.
2021.04.028.
Appendix 1. Bibliographic research strategy
 Identification of information needs: scientific evidence
concerning the pathogenesis, diagnosis and treatment
of non-alcoholic steatosis.
 Planning of the research strategy: for each topic assigned,
the researchers personally searched for the biblio-
graphic sources, using digital or paper resources if
necessary.
 Choice of tools for information retrieval: the identified
articles were obtained from the online library of the
8 Members of the guidelines panel
Institution to which the member of the experts’ panel
belongs. If not available online, the article was searched
among the paper volumes of institutional libraries or
was obtained through a direct request to the author of
the publication.
 Identification of adequate sources of information: only
articles from journals indexed on scientific search en-
gines (PubMed, Embase, Scopus) were included,
excluding non-scientific repertoires and newspapers
articles, case reports, conference abstracts not pub-
lished in-extenso. The keywords used for the research
were the following:
(1) Research topic: classification, diagnosis and prognosis of
non-alcoholic steatosis.
Free-text research keywords: liver steatosis, non-alco-
holic fatty liver, non-alcoholic fatty liver disease, non-
alcoholic steatohepatitis, classification, diagnosis,
prognosis.
BOOLEAN research string:
("Non-alcoholic Fatty Liver Disease"[Mesh] OR non
alcoholic fatty liver disease* [Title/Abstract] OR non-alco-
holic fatty liver disease* [Title/Abstract] OR nonalcoholic
fatty liver disease* [Title/Abstract] OR nonalcoholic fatty
liver* [Title/Abstract] OR non alcoholic steatohepatitis*
[Title/Abstract]) AND ("Liver Diseases" [Mesh])
[* Other: animal studies, letters, studies enrolling fewer
than 10 subjects, articles not reporting outcomes of in-
terest or primary data (editorial, unsystematic reviews),
studies with inadequate case definition or enrolling sec-
ondary steatosis (for example: steatosis from drugs, from
total parenteral nutrition etc.)]
(2) Research topic: non-invasive diagnosis of NAFLD
Descargado para Anonymous User (n/a) en Antenor Orrego Private University de ClinicalKey.es por Elsevier en julio 05, 2024. Para uso
personal exclusivamente. No se permiten otros usos sin autorización. Copyright ©2024. Elsevier Inc. Todos los derechos reservados.
Free-text research keywords: non- alcoholic fatty liver
disease, therapy, liver disease:
BOOLEAN research string:
("Non-alcoholic Fatty Liver Disease"[Mesh] OR non
alcoholic fatty liver disease* [Title/Abstract] OR non-alco-
holic fatty liver disease* [Title/Abstract] OR nonalcoholic
fatty liver disease* [Title/Abstract] OR nonalcoholic fatty
liver* [Title/Abstract] OR non alcoholic steatohepatitis*
[Title/Abstract]) AND ("Liver Cirrhosis" [Mesh] OR liver
fibrosis* [Title/Abstract] OR hepatic fibrosis* [Title/Abstract]
OR cirrhosis* [Title/Abstract] OR cirrhoses* [Title/Abstract])
AND ((16 APRI* [Title/Abstract] OR aspartate aminotrans-
ferase to platelets ratio index* [Title/Abstract]) OR (FIB-4*
[Title/Abstract] OR fibrosis-4 index* [Title/Abstract]) OR
(NAFLD fibrosis score* [Title/Abstract] OR NFS* [Title/Ab-
stract]) OR (BARD score* [Title/Abstract]) OR ("Elasticity
Imaging Techniques" [Mesh] OR Elasticity Imaging Tech-
niques [Title/Abstract]) OR (elastography* [Title/Abstract]
OR elastograph* [Title/Abstract]) OR (FibroScan* [Title/Ab-
stract] OR transient elastography* [Title/Abstract]) OR
(shear wave elastography* [Title/Abstract]) OR (magnetic
resonance elastography* [Title/Abstract] OR (38 MRE [Title/
Abstract]))
[*: Other: animal studies, letters, studies enrolling
fewer than 10 subjects, articles not reporting outcomes of
interest or primary data (editorial, unsystematic reviews),
studies with inadequate case definition or enrolling sec-
ondary steatosis (for example: steatosis from drugs, from
total parenteral nutrition etc.), articles not in English].
(3) Research topic: NAFLD therapy
Free-text reseach keywords: Non alcoholic fatty liver
disease, therapy, liver disease
BOOLEAN research string:
Practice Guidelines
("Non-alcoholic Fatty Liver Disease"[Mesh] OR non
alcoholic fatty liver disease* [Title/Abstract] OR non-alco-
holic fatty liver disease* [Title/Abstract] OR nonalcoholic
fatty liver disease* [Title/Abstract] OR nonalcoholic fatty
liver* [Title/Abstract] OR non alcoholic steatohepatitis*
[Title/Abstract]) AND ((“Therapy” [MeSH] OR “Pharmaco-
logical therapy” [MeSH] OR Drug* [Title/Abstract] OR
Therap* [Title/Abstract]) OR (exercise [Title/Abstract] OR
resistance training [Title/Abstract] OR aerobic training
[Title/Abstract] OR aerobic exercise [Title/Abstract] OR cir-
cuit training [Title/Abstract] OR walk test [Title/Abstract] OR
endurance training [Title/Abstract] OR strength training
[Title/Abstract] OR weight training [Title/Abstract]))
[*: Other: animal studies, letters, studies enrolling
fewer than 10 subjects, articles not reporting outcomes of
interest or primary data (editorial, unsystematic reviews),
studies with inadequate case definition or enrolling sec-
ondary steatosis (for example: steatosis from drugs, from
total parenteral nutrition etc.), articles not in English]
Appendix 2. Members of the guidelines panel
Coordinator: Giulio Marchesini; AISF Members: Elisabetta
Bugianesi, Patrizia Burra, Fabio Marra, Luca Miele, Anna
Alisi, Piero Vajro, Mario Masarone, Salvatore Petta, Mar-
cello Persico, Gianluca Svegliati-Baroni, Luca Valenti; SID
Members: Massimo Federici, Francesco Purrello, Ferdi-
nando Carlo Sasso, Giovanni Targher; SIO Members: Luca
Busetto, Maria Letizia Petroni, Ferruccio Santini; Metodol-
ogists: Calogero Cammà, Agostino Colli.
References
[1] Younossi ZM, Koenig AB, Abdelatif D, Fazel Y, Henry L, Wymer M.
Global epidemiology of nonalcoholic fatty liver disease-Meta-
Descargado para Anonymous User (n/a) en Antenor Orrego Private University de ClinicalKey.es por Elsevier en julio 05, 2024. Para uso
personal exclusivamente. No se permiten otros usos sin autorización. Copyright ©2024. Elsevier Inc. Todos los derechos reservados.
9
analytic assessment of prevalence, incidence, and outcomes. Hep-
atology 2016;64:73e84.
[2] Sanyal AJ, Harrison SA, Ratziu V, et al. The natural history of
advanced fibrosis due to nonalcoholic steatohepatitis: data from
the simtuzumab trials. Hepatology 2019;70:1913e27.
[3] Dongiovanni P, Stender S, Pietrelli A, et al. Causal relationship of
hepatic fat with liver damage and insulin resistance in nonalcoholic
fatty liver. J Intern Med 2018;283:356e70.
[4] European Association for the Study of the Liver, European Association
for the Study of Diabetes, European Association for the Study of Obesity.
EASL-EASD-EASO clinical practice guidelines for the management of
non-alcoholic fatty liver disease. J Hepatol 2016;64:1388e402.
[5] Eslam M, Newsome PN, Sarin SK, et al. A new definition for
metabolic dysfunction-associated fatty liver disease: an interna-
tional expert consensus statement. J Hepatol 2020;73:202e9.
[6] Bedogni G, Miglioli L, Masutti F, Tiribelli C, Marchesini G,
Bellentani S. Prevalence of and risk factors for nonalcoholic fatty
liver disease: the dionysos nutrition and liver study. Hepatology
2005;42:44e52.
[7] Pendino GM, Mariano A, Surace P, et al. Prevalence and etiology of
altered liver tests: a population-based survey in a Mediterranean
town. Hepatology 2005;41:1151e9.
[8] Caserta CA, Mele A, Surace P, et al. Association of non-alcoholic fatty
liver disease and cardiometabolic risk factors with early athero-
sclerosis in an adult population in Southern Italy. Ann Ist Super
Sanita 2017;53:77e81.
[9] Petta S, Di Marco V, Pipitone RM, et al. Prevalence and severity of
nonalcoholic fatty liver disease by transient elastography: genetic
and metabolic risk factors in a general population. Liver Int 2018;
38:2060e8.
[10] Alberti KG, Eckel RH, Grundy SM, et al. Harmonizing the metabolic
syndrome: a joint interim statement of the international diabetes
federation task force on epidemiology and prevention; national
heart, lung, and blood institute; American heart association;
World heart federation; international atherosclerosis society; and
international association for the study of obesity. Circulation
2009;120:1640e5.
[11] Colicchio P, Tarantino G, del Genio F, et al. Non-alcoholic fatty liver
disease in young adult severely obese non-diabetic patients in
South Italy. Ann Nutr Metab 2005;49:289e95.
[12] Soresi M, Noto D, Cefalu AB, et al. Nonalcoholic fatty liver and
metabolic syndrome in Italy: results from a multicentric study of
the Italian Arteriosclerosis society. Acta Diabetol 2013;50:241e9.
[13] Bellentani S, Saccoccio G, Masutti F, et al. Prevalence of and risk
factors for hepatic steatosis in Northern Italy. Ann Intern Med
2000;132:112e7.
[14] Marchesini G, Avagnina S, Barantani EG, et al. Aminotransferase
and gamma-glutamyltranspeptidase levels in obesity are associ-
ated with insulin resistance and the metabolic syndrome. J
Endocrinol Invest 2005;28:333e9.
[15] Non-alcoholic Fatty Liver Disease Study Group, Lonardo A, Bellentani S,
et al. Epidemiological modifiers of non-alcoholic fatty liver disease:
focus on high-risk groups. Dig Liver Dis 2015;47:997e1006.
[16] Younossi ZM, Golabi P, de Avila L, et al. The global epidemiology of
NAFLD and NASH in patients with type 2 diabetes: a systematic
review and meta-analysis. J Hepatol 2019;71:793e801.
[17] Targher G, Lonardo A, Byrne CD. Nonalcoholic fatty liver disease
and chronic vascular complications of diabetes mellitus. Nat Rev
Endocrinol 2018;14:99e114.
[18] Anstee QM, Targher G, Day CP. Progression of NAFLD to diabetes
mellitus, cardiovascular disease or cirrhosis. Nat Rev Gastroenterol
Hepatol 2013;10:330e44.
[19] Forlani G, Giorda C, Manti R, et al. The burden of NAFLD and its
characteristics in a nationwide population with type 2 diabetes. J
Diabetes Res 2016;2016:2931985.
[20] Targher G, Mantovani A, Pichiri I, et al. Non-alcoholic fatty liver
disease is associated with an increased prevalence of atrial
fibrillation in hospitalized patients with type 2 diabetes. Clin Sci
(Lond) 2013;125:301e9.
[21] Giorda CB, Forlani G, Manti R, et al. Trend over time in hepatic
fibrosis score in a cohort of type 2 diabetes patients. Diabetes Res
Clin Pract 2018;135:65e72.
[22] Targher G, Marchesini G, Byrne CD. Risk of type 2 diabetes in
patients with non-alcoholic fatty liver disease: causal association
or epiphenomenon? Diabetes Metab 2016;42:142e56.
10
[23] Porepa L, Ray JG, Sanchez-Romeu P, Booth GL. Newly diagnosed
diabetes mellitus as a risk factor for serious liver disease. CMAJ
2010;182:E526e31.
[24] Wild SH, Morling JR, McAllister DA, et al. Type 2 diabetes and risk
of hospital admission or death for chronic liver diseases. J Hepatol
2016;64:1358e64.
[25] Zoppini G, Fedeli U, Gennaro N, Saugo M, Targher G, Bonora E.
Mortality from chronic liver diseases in diabetes. Am J Gastro-
enterol 2014;109:1020e5.
[26] Sun DQ, Ye FZ, Kani HT, et al. Higher liver stiffness scores are
associated with early kidney dysfunction in patients with histo-
logically proven non-cirrhotic NAFLD. Diabetes Metab 2020;46:
288e95.
[27] Younossi ZM, Tampi R, Priyadarshini M, Nader F, Younossi IM,
Racila A. Burden of illness and economic model for patients with
nonalcoholic steatohepatitis in the United States. Hepatology
2019;69:564e72.
[28] Petta S, Ting J, Saragoni S, et al. Healthcare resource utilization
and costs of nonalcoholic steatohepatitis patients with advanced
liver disease in Italy. Nutr Metab Cardiovasc Dis 2020;30:
1014e22.
[29] Petta S, Ting J, Saragoni S, et al. Healthcare resource utilization and
costs of nonalcoholic steatohepatitis patients with advanced liver
disease in Italy. Nutr Metab Cardiovasc Dis 2020.
[30] Adams LA, Lymp JF, St Sauver J, et al. The natural history of
nonalcoholic fatty liver disease: a population-based cohort study.
Gastroenterology 2005;129:113e21.
[31] Younossi Z, Henry L. Contribution of alcoholic and nonalcoholic
fatty liver disease to the burden of liver-related morbidity and
mortality. Gastroenterology 2016;150:1778e85.
[32] Spahillari A, Mukamal KJ, DeFilippi C, et al. The association of lean
and fat mass with all-cause mortality in older adults: the car-
diovascular health study. Nutr Metab Cardiovasc Dis 2016;26:
1039e47.
[33] Stepanova M, Younossi ZM. Independent association between
nonalcoholic fatty liver disease and cardiovascular disease in the
US population. Clin Gastroenterol Hepatol 2012;10:646e50.
[34] Bhatia LS, Curzen NP, Calder PC, Byrne CD. Non-alcoholic fatty
liver disease: a new and important cardiovascular risk factor? Eur
Heart J 2012;33:1190e200.
[35] Lonardo A, Nascimbeni F, Mantovani A, Targher G. Hypertension,
diabetes, atherosclerosis and NASH: cause or consequence? J
Hepatol 2018;68:335e52.
[36] Kim D, Kim WR, Kim HJ, Therneau TM. Association between
noninvasive fibrosis markers and mortality among adults with
nonalcoholic fatty liver disease in the United States. Hepatology
2013;57:1357e65.
[37] Targher G, Byrne CD, Lonardo A, Zoppini G, Barbui C. Non-alco-
holic fatty liver disease and risk of incident cardiovascular disease:
a meta-analysis. J Hepatol 2016;65:589e600.
[38] Ekstedt M, Hagstrom H, Nasr P, et al. Fibrosis stage is the strongest
predictor for disease-specific mortality in NAFLD after up to 33
years of follow-up. Hepatology 2015;61:1547e54.
[39] Ballestri S, Zona S, Targher G, et al. Nonalcoholic fatty liver disease
is associated with an almost twofold increased risk of incident
type 2 diabetes and metabolic syndrome. Evidence from a sys-
tematic review and meta-analysis. J Gastroenterol Hepatol 2016;
31:936e44.
[40] Sung KC, Wild SH, Byrne CD. Resolution of fatty liver and risk of
incident diabetes. J Clin Endocrinol Metab 2013;98:3637e43.
[41] Yamazaki H, Tsuboya T, Tsuji K, Dohke M, Maguchi H. Independent
association between improvement of nonalcoholic fatty liver dis-
ease and reduced incidence of type 2 diabetes. Diabetes Care 2015;
38:1673e9.
[42] Mantovani A, Zaza G, Byrne CD, et al. Nonalcoholic fatty liver
disease increases risk of incident chronic kidney disease: a sys-
tematic review and meta-analysis. Metabolism 2018;79:64e76.
[43] Byrne CD, Targher G. NAFLD: a multisystem disease. J Hepatol
2015;62:S47e64.
[44] Sayiner M, Koenig A, Henry L, Younossi ZM. Epidemiology of
nonalcoholic fatty liver disease and nonalcoholic steatohepatitis
in the United States and the rest of the world. Clin Liver Dis 2016;
20:205e14.
[45] Global Burden of Disease 2015. Mortality and causes of death
collaborators. Global, regional, and national life expectancy, all-
Descargado para Anonymous User (n/a) en Antenor Orrego Private University de ClinicalKey.es por Elsevier en julio 05, 2024. Para uso
personal exclusivamente. No se permiten otros usos sin autorización. Copyright ©2024. Elsevier Inc. Todos los derechos reservados.
Members of the guidelines panel
cause mortality, and cause-specific mortality for 249 causes of
death, 1980-2015: a systematic analysis for the global burden of
disease study 2015. Lancet 2016;388:1459e544.
[46] Angulo P, Kleiner DE, Dam-Larsen S, et al. Liver fibrosis, but no
other histologic features, is associated with long-term outcomes
of patients with nonalcoholic fatty liver disease. Gastroenterology
2015;149:389e97. e310.
[47] Younossi ZM. Non-alcoholic fatty liver disease - a global public
health perspective. J Hepatol 2019;70:531e44.
[48] Vilar-Gomez E, Calzadilla-Bertot L, Wai-Sun Wong V, et al. Fibrosis
severity as a determinant of cause-specific mortality in patients
with advanced nonalcoholic fatty liver disease: a multi-national
cohort study. Gastroenterology 2018;155:443e57. e417.
[49] Younossi ZM, Otgonsuren M, Henry L, et al. Association of
nonalcoholic fatty liver disease (NAFLD) with hepatocellular car-
cinoma (HCC) in the United States from 2004 to 2009. Hepatology
2015;62:1723e30.
[50] Younes R, Bugianesi E. Should we undertake surveillance for HCC
in patients with NAFLD? J Hepatol 2018;68:326e34.
[51] Ioannou GN, Green P, Kerr KF, Berry K. Models estimating risk of
hepatocellular carcinoma in patients with alcohol or NAFLD-
related cirrhosis for risk stratification. J Hepatol 2019;71:523e33.
[52] Dyson J, Jaques B, Chattopadyhay D, et al. Hepatocellular cancer:
the impact of obesity, type 2 diabetes and a multidisciplinary
team. J Hepatol 2014;60:110e7.
[53] Wong RJ, Cheung R, Ahmed A. Nonalcoholic steatohepatitis is the
most rapidly growing indication for liver transplantation in pa-
tients with hepatocellular carcinoma in the U.S. Hepatology 2014;
59:2188e95.
[54] Piscaglia F, Svegliati-Baroni G, Barchetti A, et al. Clinical patterns of
hepatocellular carcinoma in nonalcoholic fatty liver disease: a
multicenter prospective study. Hepatology 2016;63:827e38.
[55] Allen AM, Hicks SB, Mara KC, Larson JJ, Therneau TM. The risk of
incident extrahepatic cancers is higher in non-alcoholic fatty liver
disease than obesity - a longitudinal cohort study. J Hepatol 2019;
71:1229e36.
[56] Younes R, Bugianesi E. NASH in lean individuals. Semin Liver Dis
2019;39:86e95.
[57] Lu FB, Zheng KI, Rios RS, Targher G, Byrne CD, Zheng MH. Global
epidemiology of lean non-alcoholic fatty liver disease: a system-
atic review and meta-analysis. J Gastroenterol Hepatol 2020;35:
2041e50.
[58] Feldman A, Eder SK, Felder TK, et al. Clinical and metabolic char-
acterization of lean caucasian subjects with non-alcoholic fatty
liver. Am J Gastroenterol 2017;112:102e10.
[59] Younossi ZM, Otgonsuren M, Venkatesan C, Mishra A. In patients
with non-alcoholic fatty liver disease, metabolically abnormal
individuals are at a higher risk for mortality while metabolically
normal individuals are not. Metabolism 2013;62:352e60.
[60] Fracanzani AL, Valenti L, Bugianesi E, et al. Risk of nonalcoholic
steatohepatitis and fibrosis in patients with nonalcoholic fatty liver
disease and low visceral adiposity. J Hepatol 2011;54:1244e9.
[61] Dela Cruz AC, Bugianesi E, George J, et al. Characteristics and long-
term prognosis of lean patients with nonalcoholic fatty liver dis-
ease. Gastroenterology 2014;146. S-909.
[62] Hagstrom H, Nasr P, Ekstedt M, et al. Risk for development of
severe liver disease in lean patients with nonalcoholic fatty liver
disease: a long-term follow-up study. Hepatol Commun 2018;2:
48e57.
[63] CNEC - Centro Nazionale per l’Eccellenza delle Cure. Manuale
metodologco per la Produzione di Linee Guida di Pratica Clinica.
Roma: ISS - Istituto Superiore di Sanità. CNEC - Centro Nazionale
per l’Eccellenza delle Cure; 2020. Available at: https://snlg.iss.it/
wp-content/uploads/2019/04/MM_v1.3.2_apr_2019.pdf.
[64] Guyatt GH, Oxman AD, Kunz R, et al. GRADE guidelines: 2.
Framing the question and deciding on important outcomes. J Clin
Epidemiol 2011;64:395e400.
[65] Moberg J, Oxman AD, Rosenbaum S, et al. The GRADE Evidence to
Decision (EtD) framework for health system and public health
decisions. Health Res Policy Syst 2018;16:45.
[66] GRADE. GRADEpro guideline development tool. Hamilton, ON,
Canada: McMaster University; 2020 [program].
[67] Whiting PF, Rutjes AW, Westwood ME, et al. QUADAS-2: a revised
tool for the quality assessment of diagnostic accuracy studies. Ann
Intern Med 2011;155:529e36.
Practice Guidelines
[68] Sterne JAC, Savovic J, Page MJ, et al. RoB 2: a revised tool for
assessing risk of bias in randomised trials. BMJ 2019;366:l4898.
[69] Sterne JA, Hernan MA, Reeves BC, et al. ROBINS-I: a tool for
assessing risk of bias in non-randomised studies of interventions.
BMJ 2016;355:i4919.
[70] Singh S, Allen AM, Wang Z, Prokop LJ, Murad MH, Loomba R.
Fibrosis progression in nonalcoholic fatty liver vs nonalcoholic
steatohepatitis: a systematic review and meta-analysis of paired-
biopsy studies. Clin Gastroenterol Hepatol 2015;13:643e54. e641-
649; quiz e639-640.
[71] Castera L, Friedrich-Rust M, Loomba R. Noninvasive assessment of
liver disease in patients with nonalcoholic fatty liver disease.
Gastroenterology 2019;156:1264e81. e1264.
[72] Verhaegh P, Bavalia R, Winkens B, Masclee A, Jonkers D, Koek G.
Noninvasive tests do not accurately differentiate nonalcoholic
steatohepatitis from simple steatosis: a systematic review and
meta-analysis. Clin Gastroenterol Hepatol 2018;16:837e61.
[73] Zheng KI, Liu WY, Pan XY, et al. Combined and sequential non-
invasive approach to diagnosing non-alcoholic steatohepatitis in
patients with non-alcoholic fatty liver disease and persistently
normal alanine aminotransferase levels. BMJ Open Diabetes Res
Care 2020;8(1):e001174.
[74] Brunt EM, Janney CG, Di Bisceglie AM, Neuschwander-Tetri BA,
Bacon BR. Nonalcoholic steatohepatitis: a proposal for grading and
staging the histological lesions. Am J Gastroenterol 1999;94:
2467e74.
[75] Bedossa P, Pathology Consortium F. Utility and appropriateness of
the fatty liver inhibition of progression (FLIP) algorithm and
steatosis, activity, and fibrosis (SAF) score in the evaluation of
biopsies of nonalcoholic fatty liver disease. Hepatology 2014;60:
565e75.
[76] Vilar-Gomez E, Chalasani N. Non-invasive assessment of non-
alcoholic fatty liver disease: Clinical prediction rules and blood-
based biomarkers. J Hepatol 2018;68:305e15.
[77] Wong VW, Adams LA, de Ledinghen V, Wong GL, Sookoian S.
Noninvasive biomarkers in NAFLD and NASH - current progress
and future promise. Nat Rev Gastroenterol Hepatol 2018;15:
461e78.
[78] Angulo P, Hui JM, Marchesini G, et al. The NAFLD fibrosis score: a
noninvasive system that identifies liver fibrosis in patients with
NAFLD. Hepatology 2007;45:846e54.
[79] Sterling RK, Lissen E, Clumeck N, et al. Development of a simple
noninvasive index to predict significant fibrosis in patients with
HIV/HCV coinfection. Hepatology 2006;43:1317e25.
[80] Lin ZH, Xin YN, Dong QJ, et al. Performance of the aspartate
aminotransferase-to-platelet ratio index for the staging of hepa-
titis C-related fibrosis: an updated meta-analysis. Hepatology
2011;53:726e36.
[81] Harrison SA, Oliver D, Arnold HL, Gogia S, Neuschwander-Tetri BA.
Development and validation of a simple NAFLD clinical scoring
system for identifying patients without advanced disease. Gut
2008;57:1441e7.
[82] Xiao G, Zhu S, Xiao X, Yan L, Yang J, Wu G. Comparison of labo-
ratory tests, ultrasound, or magnetic resonance elastography to
detect fibrosis in patients with nonalcoholic fatty liver disease: a
meta-analysis. Hepatology 2017;66:1486e501.
[83] Sun W, Cui H, Li N, et al. Comparison of FIB-4 index, NAFLD fibrosis
score and BARD score for prediction of advanced fibrosis in adult
patients with non-alcoholic fatty liver disease: a meta-analysis
study. Hepatol Res 2016;46:862e70.
[84] McPherson S, Hardy T, Dufour JF, et al. Age as a confounding factor
for the accurate non-invasive diagnosis of advanced NAFLD
fibrosis. Am J Gastroenterol 2017;112:740e51.
[85] Petta S, Wai-Sun Wong V, Bugianesi E, et al. Impact of obesity and
alanine aminotransferase levels on the diagnostic accuracy for
advanced liver fibrosis of noninvasive tools in patients with
nonalcoholic fatty liver disease. Am J Gastroenterol 2019;d114:
916e28.
[86] Joo SK, Kim W, Kim D, et al. Steatosis severity affects the diag-
nostic performances of noninvasive fibrosis tests in nonalcoholic
fatty liver disease. Liver Int 2018;38:331e41.
[87] Bertot LC, Jeffrey GP, de Boer B, et al. Diabetes impacts
prediction of cirrhosis and prognosis by non-invasive fibrosis
models in non-alcoholic fatty liver disease. Liver Int 2018;38:
1793e802.
Descargado para Anonymous User (n/a) en Antenor Orrego Private University de ClinicalKey.es por Elsevier en julio 05, 2024. Para uso
personal exclusivamente. No se permiten otros usos sin autorización. Copyright ©2024. Elsevier Inc. Todos los derechos reservados.
11
[88] Bril F, McPhaul MJ, Caulfield MP, et al. Performance of plasma
biomarkers and diagnostic panels for nonalcoholic steatohepatitis
and advanced fibrosis in patients with type 2 diabetes. Diabetes
Care 2019;43:290e7.
[89] Anstee QM, Lawitz EJ, Alkhouri N, et al. Noninvasive tests accu-
rately identify advanced fibrosis due to NASH: baseline data from
the STELLAR trials. Hepatology 2019;70:1521e30.
[90] Guillaume M, Moal V, Delabaudiere C, et al. Direct comparison of
the specialised blood fibrosis tests fibrometer(V2G) and enhanced
liver fibrosis score in patients with non-alcoholic fatty liver dis-
ease from tertiary care centres. Aliment Pharmacol Ther 2019;50:
1214e22.
[91] Wong VW, Irles M, Wong GL, et al. Unified interpretation of liver
stiffness measurement by M and XL probes in non-alcoholic fatty
liver disease. Gut 2019;68:2057e64.
[92] Boursier J, Zarski JP, de Ledinghen V, et al. Determination of reli-
ability criteria for liver stiffness evaluation by transient elastog-
raphy. Hepatology 2013;57:1182e91.
[93] Eddowes PJ, Sasso M, Allison M, et al. Accuracy of FibroScan
controlled attenuation parameter and liver stiffness measurement
in assessing steatosis and fibrosis in patients with nonalcoholic
fatty liver disease. Gastroenterology 2019;156:1717e30.
[94] Petta S, Maida M, Macaluso FS, et al. The severity of steatosis in-
fluences liver stiffness measurement in patients with nonalcoholic
fatty liver disease. Hepatology 2015;62:1101e10.
[95] Petta S, Wong VW, Camma C, et al. Improved noninvasive pre-
diction of liver fibrosis by liver stiffness measurement in patients
with nonalcoholic fatty liver disease accounting for controlled
attenuation parameter values. Hepatology 2017;65:1145e55.
[96] Karlas T, Petroff D, Sasso M, et al. Impact of controlled attenuation
parameter on detecting fibrosis using liver stiffness measurement.
Aliment Pharmacol Ther 2018;47:989e1000.
[97] Hsu C, Caussy C, Imajo K, et al. Magnetic resonance vs transient
elastography analysis of patients with nonalcoholic fatty liver
disease: a systematic review and pooled analysis of individual
participants. Clin Gastroenterol Hepatol 2019;17:630e7. e638.
[98] Cassinotto C, Boursier J, de Ledinghen V, et al. Liver stiffness in
nonalcoholic fatty liver disease: a comparison of supersonic shear
imaging, FibroScan, and ARFI with liver biopsy. Hepatology 2016;
63:1817e27.
[99] Petta S, Wong VW, Camma C, et al. Serial combination of non-
invasive tools improves the diagnostic accuracy of severe liver
fibrosis in patients with NAFLD. Aliment Pharmacol Ther 2017;46:
617e27.
[100] Petta S, Vanni E, Bugianesi E, et al. The combination of liver
stiffness measurement and NAFLD fibrosis score improves the
noninvasive diagnostic accuracy for severe liver fibrosis in pa-
tients with nonalcoholic fatty liver disease. Liver Int 2015;35:
1566e73.
[101] Boursier J, de Ledinghen V, Leroy V, et al. A stepwise algorithm
using an at-a-glance first-line test for the non-invasive diagnosis
of advanced liver fibrosis and cirrhosis. J Hepatol 2017;66:
1158e65.
[102] Srivastava A, Gailer R, Tanwar S, et al. Prospective evaluation of a
primary care referral pathway for patients with non-alcoholic
fatty liver disease. J Hepatol 2019;71:371e8.
[103] Siddiqui MS, Yamada G, Vuppalanchi R, et al. Diagnostic accuracy
of noninvasive fibrosis models to detect change in fibrosis stage.
Clin Gastroenterol Hepatol 2019;17:1877e85. e1875.
[104] Angulo P, Bugianesi E, Bjornsson ES, et al. Simple noninvasive
systems predict long-term outcomes of patients with nonalco-
holic fatty liver disease. Gastroenterology 2013;145:782e9. e784.
[105] Hagstrom H, Nasr P, Ekstedt M, Stal P, Hultcrantz R, Kechagias S.
Accuracy of noninvasive scoring systems in assessing risk of
death and liver-related endpoints in patients with nonalcoholic
fatty liver disease. Clin Gastroenterol Hepatol 2019;17:1148e56.
e1144.
[106] Sebastiani G, Alshaalan R, Wong P, et al. Prognostic value of non-
invasive fibrosis and steatosis tools, hepatic venous pressure
gradient (HVPG) and histology in nonalcoholic steatohepatitis.
PLoS One 2015;10:e0128774.
[107] Onnerhag K, Hartman H, Nilsson PM, Lindgren S. Non-invasive
fibrosis scoring systems can predict future metabolic complica-
tions and overall mortality in non-alcoholic fatty liver disease
(NAFLD). Scand J Gastroenterol 2019;54:328e34.
12
[108] Boursier J, Vergniol J, Guillet A, et al. Diagnostic accuracy and
prognostic significance of blood fibrosis tests and liver stiffness
measurement by FibroScan in non-alcoholic fatty liver disease. J
Hepatol 2016;65:570e8.
[109] Munteanu M, Pais R, Peta V, et al. Long-term prognostic value of
the FibroTest in patients with non-alcoholic fatty liver disease,
compared to chronic hepatitis C, B, and alcoholic liver disease.
Aliment Pharmacol Ther 2018;48:1117e27.
[110] Kawamura Y, Arase Y, Ikeda K, et al. Large-scale long-term follow-
up study of Japanese patients with non-alcoholic fatty liver dis-
ease for the onset of hepatocellular carcinoma. Am J Gastro-
enterol 2012;107:253e61.
[111] Shili-Masmoudi S, Wong GL, Hiriart JB, et al. Liver stiffness
measurement predicts long-term survival and complications in
non-alcoholic fatty liver disease. Liver Int 2019;40:581e9.
[112] Petta S, Sebastiani G, Vigano M, et al. Monitoring occurrence of
liver-related events and survival by transient elastography in
patients with nonalcoholic fatty liver disease and compensated
advanced chronic liver disease. Clin Gastroenterol Hepatol 2020;
19(4). :806e815.e5.
[113] Hagstrom H, Talback M, Andreasson A, Walldius G, Hammar N.
Repeated FIB-4 measurements can help identify individuals at
risk of severe liver disease. J Hepatol 2020;73:1023e9.
[114] Eslam M, Valenti L, Romeo S. Genetics and epigenetics of NAFLD
and NASH: clinical impact. J Hepatol 2018;68:268e79.
[115] Hyysalo J, Mannisto VT, Zhou Y, et al. A population-based study
on the prevalence of NASH using scores validated against liver
histology. J Hepatol 2014;60:839e46.
[116] Mancina RM, Dongiovanni P, Petta S, et al. The MBOAT7-TMC4
variant rs641738 increases risk of nonalcoholic fatty liver disease
in individuals of European descent. Gastroenterology 2016;150:
1219e30. e1216.
[117] Abul-Husn NS, Cheng X, Li AH, et al. A protein-truncating
HSD17B13 variant and protection from chronic liver disease. N
Engl J Med 2018;378:1096e106.
[118] Valenti LV, Baselli GA. Genetics of nonalcoholic fatty liver disease:
a 2018 update. Curr Pharm Des 2018;24:4566e73.
[119] Grimaudo S, Pipitone RM, Pennisi G, et al. Association between
PNPLA3 rs738409 C>G variant and liver-related outcomes in
patients with nonalcoholic fatty liver disease. Clin Gastroenterol
Hepatol 2020;18:935e44. e933.
[120] Liu YL, Patman GL, Leathart JB, et al. Carriage of the PNPLA3
rs738409 C >G polymorphism confers an increased risk of non-
alcoholic fatty liver disease associated hepatocellular carcinoma.
J Hepatol 2013;61:75e81.
[121] Anstee QM, Liu YL, Day CP, Reeves HL. Reply to: HCC and liver
disease risk in homozygous PNPLA3 p.I148M carriers approach
monogenic inheritance. J Hepatol 2015;62:982e3.
[122] Pelusi S, Baselli G, Pietrelli A, et al. Rare pathogenic variants
predispose to hepatocellular carcinoma in nonalcoholic fatty
liver disease. Sci Rep 2019;9:3682.
[123] Pillai S, Duvvuru S, Bhatnagar P, et al. The PNPLA3 I148M variant
is associated with transaminase elevations in type 2 diabetes
patients treated with basal insulin peglispro. Pharmacogenom J
2018;18:487e93.
[124] Liu WY, Zheng KI, Pan XY, et al. Effect of PNPLA3 polymorphism
on diagnostic performance of various noninvasive markers for
diagnosing and staging nonalcoholic fatty liver disease. J Gas-
troenterol Hepatol 2020;35:1057e64.
[125] Marchesini G, Bugianesi E, Forlani G, et al. Nonalcoholic fatty
liver, steatohepatitis, and the metabolic syndrome. Hepatology
2003;37:917e23.
[126] Berentzen TL, Gamborg M, Holst C, Sorensen TI, Baker JL. Body
mass index in childhood and adult risk of primary liver cancer. J
Hepatol 2014;60:325e30.
[127] Zimmermann E, Gamborg M, Holst C, Baker JL, Sorensen TI,
Berentzen TL. Body mass index in school-aged children and the
risk of routinely diagnosed non-alcoholic fatty liver disease in
adulthood: a prospective study based on the Copenhagen school
health records register. BMJ Open 2015;5:e006998.
[128] Hagstrom H, Stal P, Hultcrantz R, Hemmingsson T, Andreasson A.
Overweight in late adolescence predicts development of severe
liver disease later in life: a 39years follow-up study. J Hepatol
2016;65:363e8.
Descargado para Anonymous User (n/a) en Antenor Orrego Private University de ClinicalKey.es por Elsevier en julio 05, 2024. Para uso
personal exclusivamente. No se permiten otros usos sin autorización. Copyright ©2024. Elsevier Inc. Todos los derechos reservados.
Members of the guidelines panel
[129] Suzuki A, Angulo P, Lymp J, et al. Chronological development of
elevated aminotransferases in a nonalcoholic population. Hep-
atology 2005;41:64e71.
[130] Wong VW, Wong GL, Yeung DK, et al. Incidence of non-alcoholic
fatty liver disease in Hong Kong: a population study with paired
proton-magnetic resonance spectroscopy. J Hepatol 2015;62:
182e9.
[131] Tsuneto A, Hida A, Sera N, et al. Fatty liver incidence and pre-
dictive variables. Hypertens Res 2010;33:638e43.
[132] Zelber-Sagi S, Lotan R, Shlomai A, et al. Predictors for incidence
and remission of NAFLD in the general population during a
seven-year prospective follow-up. J Hepatol 2012;56:1145e51.
[133] Moscatiello S, Di Luzio R, Bugianesi E, et al. Cognitive-behavioral
treatment of non-alcoholic fatty liver disease: a propensity score-
adjusted observational study. Obesity 2011;19:763e70 (Silver
Spring).
[134] Promrat K, Kleiner DE, Niemeier HM, et al. Randomized
controlled trial testing the effects of weight loss on nonalcoholic
steatohepatitis. Hepatology 2010;51:121e9.
[135] Bellentani S, Dalle Grave R, Suppini A, Marchesini G. Fatty Liver
Italian N. Behavior therapy for nonalcoholic fatty liver disease:
the need for a multidisciplinary approach. Hepatology 2008;47:
746e54.
[136] Marchesini G, Petta S, Dalle Grave R. Diet, weight loss, and liver
health in nonalcoholic fatty liver disease: pathophysiology, evi-
dence, and practice. Hepatology 2016;63:2032e43.
[137] Mazzotti A, Caletti MT, Brodosi L, et al. An internet-based
approach for lifestyle changes in patients with NAFLD: two-
year effects on weight loss and surrogate markers. J Hepatol
2018;69:1155e63.
[138] Romero-Gomez M, Zelber-Sagi S, Trenell M. Treatment of NAFLD
with diet, physical activity and exercise. J Hepatol 2017;67:
829e46.
[139] Vilar-Gomez E, Calzadilla-Bertot L, Friedman SL, et al. Improve-
ment in liver histology due to lifestyle modification is indepen-
dently associated with improved kidney function in patients with
non-alcoholic steatohepatitis. Aliment Pharmacol Ther 2017;45:
332e44.
[140] Vilar-Gomez E, Martinez-Perez Y, Calzadilla-Bertot L, et al.
Weight loss through lifestyle modification significantly reduces
features of nonalcoholic steatohepatitis. Gastroenterology 2015;
149:367e78. e365; quiz e314-365.
[141] Armstrong MJ, Gaunt P, Aithal GP, et al. Liraglutide safety and
efficacy in patients with non-alcoholic steatohepatitis (LEAN): a
multicentre, double-blind, randomised, placebo-controlled phase
2 study. Lancet 2016;387:679e90.
[142] Wong VW, Chan RS, Wong GL, et al. Community-based lifestyle
modification programme for non-alcoholic fatty liver disease: a
randomized controlled trial. J Hepatol 2013;59:536e42.
[143] Neuschwander-Tetri BA. Lifestyle modification as the primary
treatment of NASH. Clin Liver Dis 2009;13:649e65.
[144] Marchesini G, Mazzella N, Forlani G. Weight loss for a healthy
liver. Gastroenterology 2015;149:274e8.
[145] Petroni ML, Brodosi L, Barbanti FL, Di Domizio S, Petta S, Marchesini G.
Lifestyle changes for the treatment of nonalcoholic fatty liver disease e
a 2015-19 update. Curr Pharma Des 2020;26:1110e8.
[146] Vilar-Gomez E, Athinarayanan SJ, Adams RN, et al. Post hoc an-
alyses of surrogate markers of non-alcoholic fatty liver disease
(NAFLD) and liver fibrosis in patients with type 2 diabetes in a
digitally supported continuous care intervention: an open-label,
non-randomised controlled study. BMJ Open 2019;9:e023597.
[147] Wong VW, Wong GL, Chan RS, et al. Beneficial effects of lifestyle
intervention in non-obese patients with non-alcoholic fatty liver
disease. J Hepatol 2018;69:1349e56.
[148] Kontogianni MD, Tileli N, Margariti A, et al. Adherence to the
Mediterranean diet is associated with the severity of non-
alcoholic fatty liver disease. Clin Nutr 2014;33:678e83.
[149] Ryan MC, Itsiopoulos C, Thodis T, et al. The Mediterranean diet
improves hepatic steatosis and insulin sensitivity in individuals
with non-alcoholic fatty liver disease. J Hepatol 2013;59:
138e43.
[150] Gepner Y, Shelef I, Komy O, et al. The beneficial effects of Med-
iterranean diet over low-fat diet may be mediated by decreasing
hepatic fat content. J Hepatol 2019;71:379e88.
Practice Guidelines
[151] Abid A, Taha O, Nseir W, Farah R, Grosovski M, Assy N. Soft drink
consumption is associated with fatty liver disease independent of
metabolic syndrome. J Hepatol 2009;51:918e24.
[152] Zelber-Sagi S, Nitzan-Kaluski D, Goldsmith R, et al. Role of
leisure-time physical activity in nonalcoholic fatty liver disease: a
population-based study. Hepatology 2008;48:1791e8.
[153] Ryu S, Chang Y, Jung HS, et al. Relationship of sitting time and
physical activity with non-alcoholic fatty liver disease. J Hepatol
2015;63:1229e37.
[154] St George A, Bauman A, Johnston A, Farrell G, Chey T, George J.
Independent effects of physical activity in patients with nonal-
coholic fatty liver disease. Hepatology 2009;50:68e76.
[155] Hashida R, Kawaguchi T, Bekki M, et al. Aerobic vs. resistance
exercise in non-alcoholic fatty liver disease: a systematic review.
J Hepatol 2017;66:142e52.
[156] Keating SE, George J, Johnson NA. The benefits of exercise for
patients with non-alcoholic fatty liver disease. Expert Rev Gas-
troenterol Hepatol 2015;9:1247e50.
[157] Sookoian S, Castano GO, Pirola CJ. Modest alcohol consumption
decreases the risk of non-alcoholic fatty liver disease: a meta-
analysis of 43 175 individuals. Gut 2014;63:530e2.
[158] Dunn W, Sanyal AJ, Brunt EM, et al. Modest alcohol consumption
is associated with decreased prevalence of steatohepatitis in
patients with non-alcoholic fatty liver disease (NAFLD). J Hepatol
2012;57:384e91.
[159] Chang Y, Cho YK, Kim Y, et al. Nonheavy drinking and worsening
of noninvasive fibrosis markers in nonalcoholic fatty liver dis-
ease: a cohort study. Hepatology 2019;69:64e75.
[160] Chang Y, Ryu S, Kim Y, et al. Low levels of alcohol consumption,
obesity, and development of fatty liver with and without evi-
dence of advanced fibrosis. Hepatology 2020;71:861e73.
[161] Ajmera V, Belt P, Wilson LA, et al. Among patients with nonal-
coholic fatty liver disease, modest alcohol use is associated with
less improvement in histologic steatosis and steatohepatitis. Clin
Gastroenterol Hepatol 2018;16:1511e20. e1515.
[162] Xu L, Xie J, Chen S, et al. Light-to-moderate alcohol consumption
is associated with increased risk of type 2 diabetes in individuals
with nonalcoholic fatty liver disease: A nne-year cohort study.
Am J Gastroenterol 2020;115:876e84.
[163] VanWagner LB, Ning H, Allen NB, et al. Alcohol use and cardio-
vascular disease risk in patients with nonalcoholic fatty liver
disease. Gastroenterology 2017;153:1260e72. e1263.
[164] Aberg F, Puukka P, Salomaa V, et al. Risks of light and moderate
alcohol use in fatty liver disease: follow-up of population co-
horts. Hepatology 2020;71:835e48.
[165] Hajifathalian K, Torabi Sagvand B, McCullough AJ. Effect of alcohol
consumption on survival in nonalcoholic fatty liver disease: a
national prospective cohort study. Hepatology 2019;70:511e21.
[166] Ascha MS, Hanouneh IA, Lopez R, Tamimi TA, Feldstein AF,
Zein NN. The incidence and risk factors of hepatocellular carci-
noma in patients with nonalcoholic steatohepatitis. Hepatology
2010;51:1972e8.
[167] The Diabetes Prevention Program Research Group. The Diabetes
Prevention Program (DPP): description of lifestyle intervention.
Diabetes Care 2002;25:2165e71.
[168] Look AHEAD Research Group, RR W, Bolin P, et al. Cardiovascular
effects of intensive lifestyle intervention in type 2 diabetes. N
Engl J Med 2013;369:145e54.
[169] Burza MA, Romeo S, Kotronen A, et al. Long-term effect of bar-
iatric surgery on liver enzymes in the Swedish obese subjects
(SOS) study. PLoS One 2013;8:e60495.
[170] Sjostrom L, Peltonen M, Jacobson P, et al. Association of bariatric
surgery with long-term remission of type 2 diabetes and with
microvascular and macrovascular complications. JAMA 2014;311:
2297e304.
[171] Lassailly G, Caiazzo R, Buob D, et al. Bariatric surgery reduces
features of nonalcoholic steatohepatitis in morbidly obese pa-
tients. Gastroenterology 2015;149:379e88. quiz e315-376.
[172] Lassailly G, Caiazzo R, Ntandja-Wandji LC, et al. Bariatric sur-
gery provides long-term resolution of nonalcoholic steatohe-
patitis and regression of fibrosis. Gastroenterology 2020;159:
1290e301.
[173] Sjostrom L, Peltonen M, Jacobson P, et al. Bariatric surgery and
long-term cardiovascular events. JAMA 2012;307:56e65.
Descargado para Anonymous User (n/a) en Antenor Orrego Private University de ClinicalKey.es por Elsevier en julio 05, 2024. Para uso
personal exclusivamente. No se permiten otros usos sin autorización. Copyright ©2024. Elsevier Inc. Todos los derechos reservados.
13
[174] Mingrone G, Panunzi S, De Gaetano A, et al. Bariatric surgery
versus conventional medical therapy for type 2 diabetes. N Engl J
Med 2012;366:1577e85.
[175] Sjoholm K, Pajunen P, Jacobson P, et al. Incidence and remission
of type 2 diabetes in relation to degree of obesity at baseline and
2 year weight change: the Swedish Obese Subjects (SOS) study.
Diabetologia 2015;58:1448e53.
[176] Klebanoff MJ, Corey KE, Chhatwal J, Kaplan LM, Chung RT, Hur C.
Bariatric surgery for nonalcoholic steatohepatitis: a clinical and
cost-effectiveness analysis. Hepatology 2017;65:1156e64.
[177] Chalasani N, Younossi Z, Lavine JE, et al. The diagnosis and
management of nonalcoholic fatty liver disease: Practice guid-
ance from the American association for the study of liver dis-
eases. Hepatology 2018;67:328e57.
[178] Rinella ME, Tacke F, Sanyal AJ, Anstee QM, participants of the AASLD
EASL Workshop. Report on the AASLD/EASL joint workshop on clinical
trial endpoints in NAFLD. J Hepatol 2019;71:823e33.
[179] Belfort R, Harrison SA, Brown K, et al. A placebo-controlled trial
of pioglitazone in subjects with nonalcoholic steatohepatitis. N
Engl J Med 2006;355:2297e307.
[180] Aithal GP, Thomas JA, Kaye PV, et al. Randomized, placebo-
controlled trial of pioglitazone in nondiabetic subjects with
nonalcoholic steatohepatitis. Gastroenterology 2008;135:
1176e84.
[181] Ratziu V, Giral P, Jacqueminet S, et al. Rosiglitazone for nonal-
coholic steatohepatitis: one-year results of the randomized
placebo-controlled fatty liver improvement with rosiglitazone
therapy (FLIRT) trial. Gastroenterology 2008;135:100e10.
[182] Sanyal AJ, Chalasani N, Kowdley KV, et al. Pioglitazone, vitamin E,
or placebo for nonalcoholic steatohepatitis. N Engl J Med 2010;
362:1675e85.
[183] Torres DM, Jones FJ, Shaw JC, Williams CD, Ward JA, Harrison SA.
Rosiglitazone versus rosiglitazone and metformin versus rosi-
glitazone and losartan in the treatment of nonalcoholic steato-
hepatitis in humans: a 12-month randomized, prospective, open-
label trial. Hepatology 2011;54:1631e9.
[184] Sharma BC, Kumar A, Garg V, Reddy RS, Sakhuja P, Sarin SK. A
randomized controlled trial comparing efficacy of pentoxifylline
and pioglitazone on metabolic factors and liver histology in pa-
tients with non-alcoholic steatohepatitis. J Clin Exp Hepatol
2012;2:333e7.
[185] Razavizade M, Jamali R, Arj A, Matini SM, Moraveji A,
Taherkhani E. The effect of pioglitazone and metformin on liver
function tests, insulin resistance, and liver fat content in nonal-
coholic fatty liver disease: a randomized double blinded clinical
trial. Hepat Mon 2013;13:e9270.
[186] Cusi K, Orsak B, Bril F, et al. Long-term pioglitazone treatment for
patients with nonalcoholic steatohepatitis and prediabetes or
type 2 diabetes mellitus: a randomized trial. Ann Intern Med
2016;165:305e15.
[187] Musso G, Cassader M, Paschetta E, Gambino R. Pioglitazone for
advanced fibrosis in nonalcoholic steatohepatitis: new evidence,
new challenges. Hepatology 2017;65:1058e61.
[188] Yen FS, Yang YC, Hwu CM, et al. Liver-related long-term outcomes
of thiazolidinedione use in persons with type 2 diabetes. Liver Int
2020;40:1089e97.
[189] Dormandy JA, Charbonnel B, Eckland DJ, et al. Secondary pre-
vention of macrovascular events in patients with type 2 diabetes
in the proactive study (PROspective pioglitAzone clinical trial in
macrovascular events): a randomised controlled trial. Lancet
2005;366:1279e89.
[190] Kernan WN, Viscoli CM, Furie KL, et al. Pioglitazone after
ischemic stroke or transient ischemic attack. N Engl J Med 2016;
374:1321e31.
[191] Lewis JD, Habel LA, Quesenberry CP, et al. Pioglitazone use and
risk of bladder cancer and other common cancers in persons with
diabetes. JAMA 2015;314:265e77.
[192] Billington EO, Grey A, Bolland MJ. The effect of thiazolidinediones
on bone mineral density and bone turnover: systematic review
and meta-analysis. Diabetologia 2015;58:2238e46.
[193] Liao HW, Saver JL, Wu YL, Chen TH, Lee M, Ovbiagele B. Piogli-
tazone and cardiovascular outcomes in patients with insulin
resistance, pre-diabetes and type 2 diabetes: a systematic review
and meta-analysis. BMJ Open 2017;7:e013927.
14
[194] Mahady SE, Wong G, Craig JC, George J. Pioglitazone and vitamin
E for nonalcoholic steatohepatitis: a cost utility analysis. Hep-
atology 2012;56:2172e9.
[195] Hoofnagle JH, Van Natta ML, Kleiner DE, et al. Vitamin E and
changes in serum alanine aminotransferase levels in patients
with non-alcoholic steatohepatitis. Aliment Pharmacol Ther
2013;38:134e43.
[196] Sato K, Gosho M, Yamamoto T, et al. Vitamin E has a beneficial
effect on nonalcoholic fatty liver disease: a meta-analysis of
randomized controlled trials. Nutrition 2015;31:923e30.
[197] Xu R, Tao A, Zhang S, Deng Y, Chen G. Association between
vitamin E and non-alcoholic steatohepatitis: a meta-analysis. Int
J Clin Exp Med 2015;8:3924e34.
[198] Bril F, Biernacki DM, Kalavalapalli S, et al. Role of vitamin E
for nonalcoholic steatohepatitis in patients with type 2
diabetes: a randomized controlled trial. Diabetes Care 2019;
42:1481e8.
[199] Vilar-Gomez E, Vuppalanchi R, Gawrieh S, et al. Vitamin E im-
proves transplant-free survival and hepatic decompensation
among patients with nonalcoholic steatohepatitis and advanced
fibrosis. Hepatology 2018;71:495e509.
[200] Bjelakovic G, Nikolova D, Gluud LL, Simonetti RG, Gluud C.
Mortality in randomized trials of antioxidant supplements for
primary and secondary prevention: systematic review and meta-
analysis. JAMA 2007;297:842e57.
[201] Schurks M, Glynn RJ, Rist PM, Tzourio C, Kurth T. Effects of
vitamin E on stroke subtypes: meta-analysis of randomised
controlled trials. BMJ 2010;341:c5702.
[202] Klein EA, Thompson IM, Tangen CM, et al. Vitamin E and the risk
of prostate cancer: the selenium and vitamin E cancer prevention
trial (SELECT). JAMA 2011;306:1549e56.
[203] Dufour JF, Oneta CM, Gonvers JJ, et al. Randomized placebo-
controlled trial of ursodeoxycholic acid with vitamin E in
nonalcoholic steatohepatitis. Clin Gastroenterol Hepatol 2006;4:
1537e43.
[204] Lindor KD, Kowdley KV, Heathcote EJ, et al. Ursodeoxycholic acid
for treatment of nonalcoholic steatohepatitis: results of a ran-
domized trial. Hepatology 2004;39:770e8.
[205] Leuschner UF, Lindenthal B, Herrmann G, et al. High-dose urso-
deoxycholic acid therapy for nonalcoholic steatohepatitis: a
double-blind, randomized, placebo-controlled trial. Hepatology
2010;52:472e9.
[206] Ratziu V, de Ledinghen V, Oberti F, et al. A randomized controlled
trial of high-dose ursodesoxycholic acid for nonalcoholic stea-
tohepatitis. J Hepatol 2011;54:1011e9.
[207] Younossi ZM, Ratziu V, Loomba R, et al. Obeticholic acid for the
treatment of non-alcoholic steatohepatitis: interim analysis from
a multicentre, randomised, placebo-controlled phase 3 trial.
Lancet 2019;394:2184e96.
[208] Neuschwander-Tetri BA, Loomba R, Sanyal AJ, et al. Farnesoid X
nuclear receptor ligand obeticholic acid for non-cirrhotic, non-
alcoholic steatohepatitis (FLINT): a multicentre, randomised,
placebo-controlled trial. Lancet 2015;385:956e65.
[209] Intercept pharmaceuticals: update on intercept’s NDA submission to
the FDA. Globe Newswire; 2020. https://ir.interceptpharma.com/
news-releases/news-release-details/intercept-receives-complete-
response-letter-fda-obeticholic-acid.
[210] Bugianesi E, Gentilcore E, Manini R, et al. A randomized
controlled trial of metformin versus vitamin E or prescriptive diet
in nonalcoholic fatty liver disease. Am J Gastroenterol 2005;100:
1082e90.
[211] Haukeland JW, Konopski Z, Eggesbo HB, et al. Metformin in pa-
tients with non-alcoholic fatty liver disease: a randomized,
controlled trial. Scand J Gastroenterol 2009;44:853e60.
[212] Lavine JE, Schwimmer JB, Van Natta ML, et al. Effect of vitamin E
or metformin for treatment of nonalcoholic fatty liver disease in
children and adolescents: the TONIC randomized controlled trial.
JAMA 2011;305:1659e68.
[213] Omer Z, Cetinkalp S, Akyildiz M, et al. Efficacy of insulin-
sensitizing agents in nonalcoholic fatty liver disease. Eur J Gas-
troenterol Hepatol 2010;22:18e23.
[214] Rana H, Yadav SS, Reddy HD, Singhal S, Singh DK, Usman K.
Comparative effect of insulin sensitizers and statin on metabolic
profile and ultrasonographical score in non alcoholic fatty liver
disease. J Clin Diagn Res 2016;10:OC19e23.
Descargado para Anonymous User (n/a) en Antenor Orrego Private University de ClinicalKey.es por Elsevier en julio 05, 2024. Para uso
personal exclusivamente. No se permiten otros usos sin autorización. Copyright ©2024. Elsevier Inc. Todos los derechos reservados.
Members of the guidelines panel
[215] Zhang ZJ, Zheng ZJ, Shi R, Su Q, Jiang Q, Kip KE. Metformin for
liver cancer prevention in patients with type 2 diabetes: a sys-
tematic review and meta-analysis. J Clin Endocrinol Metab 2012;
97:2347e53.
[216] Cui J, Philo L, Nguyen P, et al. Sitagliptin vs. placebo for non-
alcoholic fatty liver disease: a randomized controlled trial. J
Hepatol 2016;65:369e76.
[217] Macauley M, Hollingsworth KG, Smith FE, et al. Effect of vildagliptin
on hepatic steatosis. J Clin Endocrinol Metab 2015;100:1578e85.
[218] Deng XL, Ma R, Zhu HX, Zhu J. Short article: a randomized-
controlled study of sitagliptin for treating diabetes mellitus
complicated by nonalcoholic fatty liver disease. Eur J Gastro-
enterol Hepatol 2017;29:297e301.
[219] Yan J, Yao B, Kuang H, et al. Liraglutide, sitagliptin, and insulin
glargine added to metformin: the effect on body weight and
intrahepatic lipid in patients with type 2 diabetes mellitus and
nonalcoholic fatty liver disease. Hepatology 2019;69:2414e26.
[220] American Diabetes Association. Pharmacologic approaches to
glycemic treatment: standards of medical care in diabetes-2019.
Diabetes Care 2019;42:S90e102.
[221] Armstrong MJ, Houlihan DD, Rowe IA, et al. Safety and efficacy of
liraglutide in patients with type 2 diabetes and elevated liver
enzymes: individual patient data meta-analysis of the LEAD
program. Aliment Pharmacol Ther 2013;37:234e42.
[222] Shao N, Kuang HY, Hao M, Gao XY, Lin WJ, Zou W. Benefits of
exenatide on obesity and non-alcoholic fatty liver disease with
elevated liver enzymes in patients with type 2 diabetes. Diabetes
Metab Res Rev 2014;30:521e9.
[223] Dutour A, Abdesselam I, Ancel P, et al. Exenatide decreases liver
fat content and epicardial adipose tissue in patients with obesity
and type 2 diabetes: a prospective randomized clinical trial using
magnetic resonance imaging and spectroscopy. Diabetes Obes
Metab 2016;18:882e91.
[224] Frossing S, Nylander M, Chabanova E, et al. Effect of liraglutide on
ectopic fat in polycystic ovary syndrome: a randomized clinical
trial. Diabetes Obes Metab 2018;20:215e8.
[225] Feng W, Gao C, Bi Y, et al. Randomized trial comparing the effects
of gliclazide, liraglutide, and metformin on diabetes with non-
alcoholic fatty liver disease. J Diabetes 2017;9:800e9.
[226] Newsome P, Francque S, Harrison S, et al. Effect of semaglutide on liver
enzymes and markers of inflammation in subjects with type 2 dia-
betes and/or obesity. Aliment Pharmacol Ther 2019;50:193e203.
[227] Newsome PN, Buchholtz K, Cusi K, et al. A placebo-controlled
trial of subcutaneous semaglutide in nonalcoholic steatohepati-
tis. N Engl J Med 2021;384(12):1113e24.
[228] Kristensen SL, Rorth R, Jhund PS, et al. Cardiovascular, mortality,
and kidney outcomes with GLP-1 receptor agonists in patients
with type 2 diabetes: a systematic review and meta-analysis of
cardiovascular outcome trials. Lancet Diabetes Endocrinol 2019;
7:776e85.
[229] Sattar N, Fitchett D, Hantel S, George JT, Zinman B. Empagliflozin
is associated with improvements in liver enzymes potentially
consistent with reductions in liver fat: results from randomised
trials including the EMPA-REG OUTCOME(R) trial. Diabetologia
2018;61:2155e63.
[230] Ito D, Shimizu S, Inoue K, et al. Comparison of ipragliflozin and
pioglitazone effects on nonalcoholic fatty liver disease in patients
with type 2 diabetes: a randomized, 24-week, open-label, active-
controlled trial. Diabetes Care 2017;40:1364e72.
[231] Kuchay MS, Krishan S, Mishra SK, et al. Effect of empagliflozin on
liver fat in patients with type 2 diabetes and nonalcoholic fatty
liver disease: a randomized controlled trial (E-LIFT trial). Dia-
betes Care 2018;41:1801e8.
[232] Eriksson JW, Lundkvist P, Jansson PA, et al. Effects of dapagliflozin
and n-3 carboxylic acids on non-alcoholic fatty liver disease in
people with type 2 diabetes: a double-blind randomised
placebo-controlled study. Diabetologia 2018;61:1923e34.
[233] Bolinder J, Ljunggren O, Kullberg J, et al. Effects of dapagliflozin
on body weight, total fat mass, and regional adipose tissue dis-
tribution in patients with type 2 diabetes mellitus with inade-
quate glycemic control on metformin. J Clin Endocrinol Metab
2012;97:1020e31.
[234] Cusi K, Bril F, Barb D, et al. Effect of canagliflozin treatment on
hepatic triglyceride content and glucose metabolism in patients
with type 2 diabetes. Diabetes Obes Metab 2019;21:812e21.
Practice Guidelines
[235] Leiter LA, Forst T, Polidori D, Balis DA, Xie J, Sha S. Effect of
canagliflozin on liver function tests in patients with type 2 dia-
betes. Diabetes Metab 2016;42:25e32.
[236] Wilding JP, Charpentier G, Hollander P, et al. Efficacy and safety of
canagliflozin in patients with type 2 diabetes mellitus inade-
quately controlled with metformin and sulphonylurea: a rand-
omised trial. Int J Clin Pract 2013;67:1267e82.
[237] Shimizu M, Suzuki K, Kato K, et al. Evaluation of the effects of
dapagliflozin, a sodium-glucose co-transporter-2 inhibitor, on
hepatic steatosis and fibrosis using transient elastography in
patients with type 2 diabetes and non-alcoholic fatty liver dis-
ease. Diabetes Obes Metab 2019;21:285e92.
[238] Bolinder J, Ljunggren O, Johansson L, et al. Dapagliflozin main-
tains glycaemic control while reducing weight and body fat mass
over 2 years in patients with type 2 diabetes mellitus inade-
quately controlled on metformin. Diabetes Obes Metab 2014;16:
159e69.
[239] Kluger AY, Tecson KM, Lee AY, et al. Class effects of SGLT2
inhibitors on cardiorenal outcomes. Cardiovasc Diabetol
2019;18:99.
[240] Haldar D, Kern B, Hodson J, et al. Outcomes of liver trans-
plantation for non-alcoholic steatohepatitis: a European liver
transplant registry study. J Hepatol 2019;71:313e22.
[241] Wang X, Li J, Riaz DR, Shi G, Liu C, Dai Y. Outcomes of liver
transplantation for nonalcoholic steatohepatitis: a systematic
review and meta-analysis. Clin Gastroenterol Hepatol 2014;12:
394e402. e391.
[242] Tsochatzis E, Coilly A, Nadalin S, et al. International Liver
Transplantation consensus statement on end-stage liver disease
due to nonalcoholic steatohepatitis and liver transplantation.
Transplantation 2019;103:45e56.
[243] Stine JG, Wentworth BJ, Zimmet A, et al. Systematic review with
meta-analysis: risk of hepatocellular carcinoma in non-alcoholic
steatohepatitis without cirrhosis compared to other liver dis-
eases. Aliment Pharmacol Ther 2018;48:696e703.
[244] Kulik L, El-Serag HB. Epidemiology and management of hepato-
cellular carcinoma. Gastroenterology 2019;156:477e91. e471.
[245] An J, Shim JH, Kim SO, et al. Prevalence and prediction of coro-
nary artery disease in patients with liver cirrhosis: a registry-
based matched case-control study. Circulation 2014;130:
1353e62.
[246] Patel SS, Nabi E, Guzman L, et al. Coronary artery disease in
decompensated patients undergoing liver transplantation eval-
uation. Liver Transpl 2018;24:333e42.
[247] Konerman MA, Fritze D, Weinberg RL, Sonnenday CJ, Sharma P.
Incidence of and risk assessment for adverse cardiovascular
outcomes after liver transplantation: a systematic review.
Transplantation 2017;101:1645e57.
[248] Yotti R, Ripoll C, Bermejo J, Banares R. Cardiac function, a key
component in evaluation for liver transplant. Liver Transpl 2018;
24:7e8.
[249] Carey WD, Dumot JA, Pimentel RR, et al. The prevalence of cor-
onary artery disease in liver transplant candidates over age 50.
Transplantation 1995;59:859e64.
[250] Plotkin JS, Scott VL, Pinna A, Dobsch BP, De Wolf AM, Kang Y.
Morbidity and mortality in patients with coronary artery disease
undergoing orthotopic liver transplantation. Liver Transpl Surg
1996;2:426e30.
[251] Hayes SW, De Lorenzo A, Hachamovitch R, et al. Prognostic im-
plications of combined prone and supine acquisitions in patients
with equivocal or abnormal supine myocardial perfusion SPECT. J
Nucl Med 2003;44:1633e40.
[252] Senzolo M, Bassanello M, Graziotto A, et al. Microvascular auto-
nomic dysfunction may justify false-positive stress myocardial
perfusion imaging in patients with liver cirrhosis undergoing
liver transplantation. Transplant Proc 2008;40:1916e7.
[253] Germani G, Laryea M, Rubbia-Brandt L, et al. Management of
recurrent and de novo NAFLD/NASH after liver transplantation.
Transplantation 2019;103:57e67.
[254] Fleisher LA, Fleischmann KE, Auerbach AD, et al. 2014 ACC/AHA
guideline on perioperative cardiovascular evaluation and man-
agement of patients undergoing noncardiac surgery: executive
summary: a report of the American college of cardiology/Amer-
ican heart association task force on practice guidelines. Circula-
tion 2014;130:2215e45.
Descargado para Anonymous User (n/a) en Antenor Orrego Private University de ClinicalKey.es por Elsevier en julio 05, 2024. Para uso
personal exclusivamente. No se permiten otros usos sin autorización. Copyright ©2024. Elsevier Inc. Todos los derechos reservados.
15
[255] Chalasani N, Younossi Z, Lavine JE, et al. The diagnosis and manage-
ment of non-alcoholic fatty liver disease: practice guideline by the
American association for the study of liver diseases, American college
of gastroenterology, and the American gastroenterological associa-
tion. Hepatology 2012;55:2005e23.
[256] Nair S, Verma S, Thuluvath PJ. Obesity and its effect on survival in
patients undergoing orthotopic liver transplantation in the
United States. Hepatology 2002;35:105e9.
[257] Ratziu V, Ghabril M, Romero-Gomez M, Svegliati-Baroni G. Rec-
ommendations for management and treatment of nonalcoholic
steatohepatitis. Transplantation 2019;103:28e38.
[258] Younossi ZM, Stepanova M, Saab S, et al. The impact of type 2
diabetes and obesity on the long-term outcomes of more than 85
000 liver transplant recipients in the US. Aliment Pharmacol
Ther 2014;40:686e94.
[259] Mosko JD, Nguyen GC. Increased perioperative mortality
following bariatric surgery among patients with cirrhosis. Clin
Gastroenterol Hepatol 2011;9:897e901.
[260] Lin MY, Tavakol MM, Sarin A, et al. Laparoscopic sleeve gastrec-
tomy is safe and efficacious for pretransplant candidates. Surg
Obes Relat Dis 2013;9:653e8.
[261] Takata MC, Campos GM, Ciovica R, et al. Laparoscopic bariatric
surgery improves candidacy in morbidly obese patients awaiting
transplantation. Surg Obes Relat Dis 2008;4:159e64. discussion
164-155.
[262] Dziodzio T, Biebl M, Ollinger R, Pratschke J, Denecke C. The role of
bariatric surgery in abdominal organ transplantation-the next
big challenge? Obes Surg 2017;27:2696e706.
[263] Heimbach JK, Watt KD, Poterucha JJ, et al. Combined liver
transplantation and gastric sleeve resection for patients with
medically complicated obesity and end-stage liver disease. Am J
Transplant 2013;13:363e8.
[264] Bedogni G, Bellentani S, Miglioli L, et al. The Fatty Liver Index: a
simple and accurate predictor of hepatic steatosis in the general
population. BMC Gastroenterol 2006;6:33.
[265] Fedchuk L, Nascimbeni F, Pais R, et al. Performance and limita-
tions of steatosis biomarkers in patients with nonalcoholic fatty
liver disease. Aliment Pharmacol Ther 2014;40:1209e22.
[266] Hernaez R, Lazo M, Bonekamp S, et al. Diagnostic accuracy and
reliability of ultrasonography for the detection of fatty liver: a
meta-analysis. Hepatology 2011;54:1082e90.
[267] Ajmera V, Park CC, Caussy C, et al. Magnetic resonance imaging
proton density fat fraction associates with progression of fibrosis
in patients with nonalcoholic fatty liver disease. Gastroenter-
ology 2018;155:307e10. e302.
[268] Ryan CK, Johnson LA, Germin BI, Marcos A. One hundred
consecutive hepatic biopsies in the workup of living donors for
right lobe liver transplantation. Liver Transpl 2002;8:1114e22.
[269] Lee SS, Park SH. Radiologic evaluation of nonalcoholic fatty liver
disease. World J Gastroenterol 2014;20:7392e402.
[270] Gu J, Liu S, Du S, et al. Diagnostic value of MRI-PDFF for hepatic
steatosis in patients with non-alcoholic fatty liver disease: a
meta-analysis. Eur Radiol 2019;29:3564e73.
[271] Loomba R. Role of imaging-based biomarkers in NAFLD: recent
advances in clinical application and future research directions. J
Hepatol 2018;68:296e304.
[272] Pu K, Wang Y, Bai S, et al. Diagnostic accuracy of controlled
attenuation parameter (CAP) as a non-invasive test for steatosis
in suspected non-alcoholic fatty liver disease: a systematic re-
view and meta-analysis. BMC Gastroenterol 2019;19:51.
[273] Petroff D, Blank V, Newsome PN, et al. Assessment of hepatic
steatosis by controlled attenuation parameter using the M and XL
probes: an individual patient data meta-analysis. Lancet Gas-
troenterol Hepatol 2021;6:185e98.
[274] Caussy C, Alquiraish MH, Nguyen P, et al. Optimal threshold of
controlled attenuation parameter with MRI-PDFF as the gold
standard for the detection of hepatic steatosis. Hepatology 2018;
67:1348e59.
[275] Chan WK, Nik Mustapha NR, Mahadeva S, Wong VW, Cheng JY,
Wong GL. Can the same controlled attenuation parameter cut-
offs be used for M and XL probes for diagnosing hepatic stea-
tosis? J Gastroenterol Hepatol 2018;33:1787e94.
[276] Karlas T, Petroff D, Sasso M, et al. Individual patient data meta-
analysis of controlled attenuation parameter (CAP) technology
for assessing steatosis. J Hepatol 2017;66:1022e30.
16 Members of the guidelines panel

[277] Wilson JMG, Jungner G. Principles and practice of screening for
disease. Geneva: World Health Organization; 1968.
[278] Nascimbeni F, Pais R, Bellentani S, et al. From NAFLD in clinical
practice to answers from guidelines. J Hepatol 2013;59:859e71.
[279] Kanwal F, Kramer J, Li L, et al. Effect of metabolic traits on the risk
of cirrhosis and hepatocellular cancer in non-alcoholic fatty liver
disease. Hepatology 2020;71:808e19.
[280] Usher-Smith JA, Sharp SJ, Griffin SJ. The spectrum effect in tests for risk
prediction, screening, and diagnosis. BMJ 2016;353:i3139.
[281] Harris R, Harman DJ, Card TR, Aithal GP, Guha IN. Prevalence of
clinically significant liver disease within the general population,
as defined by non-invasive markers of liver fibrosis: a systematic
review. Lancet Gastroenterol Hepatol 2017;2:288e97.
[282] Standing HC, Jarvis H, Orr J, et al. GPs’ experiences and percep-
tions of early detection of liver disease: a qualitative study in
primary care. Br J Gen Pract 2018;68:e743e9.
[283] Srivastava A, Jong S, Gola A, et al. Cost-comparison analysis
of FIB-4, ELF and fibroscan in community pathways for
non-alcoholic fatty liver disease. BMC Gastroenterol 2019;
19:122.
[284] Petroni ML, Brodosi L, Bugianesi E, Marchesini G. Management of
non-alcoholic fatty liver disease. BMJ 2021;372:m4747.

Descargado para Anonymous User (n/a) en Antenor Orrego Private University de ClinicalKey.es por Elsevier en julio 05, 2024. Para uso
personal exclusivamente. No se permiten otros usos sin autorización. Copyright ©2024. Elsevier Inc. Todos los derechos reservados.